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Zhang S, Guo L, Tao R, Liu S. Ferroptosis-targeting drugs in breast cancer. J Drug Target 2025; 33:42-59. [PMID: 39225187 DOI: 10.1080/1061186x.2024.2399181] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2024] [Revised: 07/07/2024] [Accepted: 08/26/2024] [Indexed: 09/04/2024]
Abstract
In 2020, breast cancer surpassed lung cancer as the most common cancer in the world for the first time. Due to the resistance of some breast cancer cell lines to apoptosis, the therapeutic effect of anti-breast cancer drugs is limited. According to recent report, the susceptibility of breast cancer cells to ferroptosis affects the progress, prognosis and drug resistance of breast cancer. For instance, roblitinib induces ferroptosis of trastuzumab-resistant human epidermal growth factor receptor 2 (HER2)-positive breast cancer cells by diminishing fibroblast growth factor receptor 4 (FGFR4) expression, thereby augmenting the susceptibility of these cells to HER2-targeted therapies. In tamoxifen-resistant breast cancer cells, Fascin exacerbates their resistance by repressing solute carrier family 7 member 11 (SLC7A11) expression, which in turn heightens their responsiveness to tamoxifen. In recent years, Chinese herbs extracts and therapeutic drugs have been demonstrated to elicit ferroptosis in breast cancer cells by modulating a spectrum of regulatory factors pertinent to ferroptosis, including SLC7A11, glutathione peroxidase 4 (GPX4), acyl-CoA synthetase long chain family member 4 (ACSL4), and haem oxygenase 1 (HO-1). Here, we review the roles and mechanisms of Chinese herbal extracts and therapeutic drugs in regulating ferroptosis in breast cancer, providing potential therapeutic options for anti-breast cancer.
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Affiliation(s)
- Shuxian Zhang
- Chronic Disease Research Center, Medical College, Dalian University, Dalian, China
| | - Lijuan Guo
- Chronic Disease Research Center, Medical College, Dalian University, Dalian, China
| | - Ran Tao
- Department of Anatomy, Medical College, Dalian University, Dalian, China
| | - Shuangping Liu
- Chronic Disease Research Center, Medical College, Dalian University, Dalian, China
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2
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Kubatka P, Koklesova L, Mazurakova A, Brockmueller A, Büsselberg D, Kello M, Shakibaei M. Cell plasticity modulation by flavonoids in resistant breast carcinoma targeting the nuclear factor kappa B signaling. Cancer Metastasis Rev 2024; 43:87-113. [PMID: 37789138 PMCID: PMC11016017 DOI: 10.1007/s10555-023-10134-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Accepted: 08/31/2023] [Indexed: 10/05/2023]
Abstract
Cancer cell plasticity plays a crucial role in tumor initiation, progression, and metastasis and is implicated in the multiple cancer defense mechanisms associated with therapy resistance and therapy evasion. Cancer resistance represents one of the significant obstacles in the clinical management of cancer. Some reversal chemosensitizing agents have been developed to resolve this serious clinical problem, but they have not yet been proven applicable in oncological practice. Activated nuclear factor kappa B (NF-κB) is a frequently observed biomarker in chemoresistant breast cancer (BC). Therefore, it denotes an attractive cellular target to mitigate cancer resistance. We summarize that flavonoids represent an essential class of phytochemicals that act as significant regulators of NF-κB signaling and negatively affect the fundamental cellular processes contributing to acquired cell plasticity and drug resistance. In this regard, flavokawain A, icariin, alpinetin, genistein, wogonin, apigenin, oroxylin A, xanthohumol, EGCG, hesperidin, naringenin, orientin, luteolin, delphinidin, fisetin, norwogonin, curcumin, cardamonin, methyl gallate and catechin-3-O-gallate, ampelopsin, puerarin, hyperoside, baicalein, paratocarpin E, and kaempferol and also synthetic flavonoids such as LFG-500 and 5,3'-dihydroxy-3,6,7,8,4'-pentamethoxyflavone have been reported to specifically interfere with the NF-κB pathway with complex signaling consequences in BC cells and could be potentially crucial in re-sensitizing unresponsive BC cases. The targeting NF-κB by above-mentioned flavonoids includes the modification of tumor microenvironment and epithelial-mesenchymal transition, growth factor receptor regulations, and modulations of specific pathways such as PI3K/AKT, MAP kinase/ERK, and Janus kinase/signal transduction in BC cells. Besides that, NF-κB signaling in BC cells modulated by flavonoids has also involved the regulation of ATP-binding cassette transporters, apoptosis, autophagy, cell cycle, and changes in the activity of cancer stem cells, oncogenes, or controlling of gene repair. The evaluation of conventional therapies in combination with plasticity-regulating/sensitizing agents offers new opportunities to make significant progress towards a complete cure for cancer.
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Affiliation(s)
- Peter Kubatka
- Department of Histology and Embryology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia.
| | - Lenka Koklesova
- Clinic of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
| | - Alena Mazurakova
- Department of Anatomy, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
| | - Aranka Brockmueller
- Chair of Vegetative Anatomy, Institute of Anatomy, Faculty of Medicine, LMU Munich, Pettenkoferstr. 11, D-80336, Munich, Germany
| | - Dietrich Büsselberg
- Department of Physiology and Biophysics, Weill Cornell Medicine in Qatar, Qatar Foundation, Doha, Qatar
| | - Martin Kello
- Department of Pharmacology, Faculty of Medicine, Pavol Jozef Safarik University, Kosice, Slovakia.
| | - Mehdi Shakibaei
- Chair of Vegetative Anatomy, Institute of Anatomy, Faculty of Medicine, LMU Munich, Pettenkoferstr. 11, D-80336, Munich, Germany.
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Chang CM, Chang CC, Lam HYP, Peng SY, Lai YH, Hsiang BD, Liao YY, Hsu HJ, Jiang SJ. Therapeutic Peptide RF16 Derived from CXCL8 Inhibits MDA-MB-231 Cell Invasion and Metastasis. Int J Mol Sci 2023; 24:14029. [PMID: 37762330 PMCID: PMC10531501 DOI: 10.3390/ijms241814029] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Revised: 09/08/2023] [Accepted: 09/11/2023] [Indexed: 09/29/2023] Open
Abstract
Interleukin (IL)-8 plays a vital role in regulating inflammation and breast cancer formation by activating CXCR1/2. We previously designed an antagonist peptide, (RF16), to inhibits the activation of downstream signaling pathways by competing with IL-8 in binding to CXCR1/2, thereby inhibiting IL-8-induced chemoattractant monocyte binding. To evaluate the effect of the RF16 peptide on breast cancer progression, triple-negative MDA-MB-231 and ER-positive MCF-7 breast cancer cells were used to investigate whether RF16 can inhibit the IL-8-induced breast cancer metastasis. Using growth, proliferation, and invasiveness assays, the results revealed that RF16 reduced cell proliferation, migration, and invasiveness in MDA-MB-231 cells. The RF16 peptide also regulated the protein and mRNA expressions of epithelial-mesenchymal transition (EMT) markers in IL-8-stimulated MDA-MB-231 cells. It also inhibited downstream IL-8 signaling and the IL-8-induced inflammatory response via the mitogen-activated protein kinase (MAPK) and Phosphoinositide 3-kinase (PI3K) pathways. In the xenograft tumor mouse model, RF16 synergistically reinforces the antitumor efficacy of docetaxel by improving mouse survival and retarding tumor growth. Our results indicate that RF16 significantly inhibited IL-8-stimulated cell growth, migration, and invasion in MDA-MB-231 breast cancer cells by blocking the activation of p38 and AKT cascades. It indicated that the RF16 peptide may serve as a new supplementary drug for breast cancer.
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Affiliation(s)
- Chun-Ming Chang
- Department of General Surgery, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 97004, Taiwan;
- Institute of Medical Sciences, Tzu Chi University, Hualien 97004, Taiwan
| | - Chun-Chun Chang
- Department of Laboratory Medicine, Hualien Tzu Chi Hospital, Hualien 97004, Taiwan;
- Department of Laboratory Medicine and Biotechnology, College of Medicine, Tzu Chi University, Hualien 97004, Taiwan
| | - Ho Yin Pekkle Lam
- Department of Biochemistry, School of Medicine, Tzu Chi University, Hualien 97004, Taiwan; (H.Y.P.L.); (S.-Y.P.); (Y.-H.L.)
- Master Program in Biomedical Sciences, School of Medicine, Tzu Chi University, Hualien 97004, Taiwan;
| | - Shih-Yi Peng
- Department of Biochemistry, School of Medicine, Tzu Chi University, Hualien 97004, Taiwan; (H.Y.P.L.); (S.-Y.P.); (Y.-H.L.)
- Master Program in Biomedical Sciences, School of Medicine, Tzu Chi University, Hualien 97004, Taiwan;
| | - Yi-Hsuan Lai
- Department of Biochemistry, School of Medicine, Tzu Chi University, Hualien 97004, Taiwan; (H.Y.P.L.); (S.-Y.P.); (Y.-H.L.)
| | - Bi-Da Hsiang
- Department of Molecular Biology and Human Genetics, School of Medicine, Tzu Chi University, Hualien 97004, Taiwan;
| | - Yu-Yi Liao
- Master Program in Biomedical Sciences, School of Medicine, Tzu Chi University, Hualien 97004, Taiwan;
| | - Hao-Jen Hsu
- Department of Biomedical Sciences and Engineering, College of Medicine, Tzu Chi University, Hualien 97004, Taiwan;
| | - Shinn-Jong Jiang
- Department of Biochemistry, School of Medicine, Tzu Chi University, Hualien 97004, Taiwan; (H.Y.P.L.); (S.-Y.P.); (Y.-H.L.)
- Master Program in Biomedical Sciences, School of Medicine, Tzu Chi University, Hualien 97004, Taiwan;
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Sweeney C, Lazennec G, Vogel CFA. Environmental exposure and the role of AhR in the tumor microenvironment of breast cancer. Front Pharmacol 2022; 13:1095289. [PMID: 36588678 PMCID: PMC9797527 DOI: 10.3389/fphar.2022.1095289] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Accepted: 12/05/2022] [Indexed: 12/23/2022] Open
Abstract
Activation of the aryl hydrocarbon receptor (AhR) through environmental exposure to chemicals including polycyclic aromatic hydrocarbons (PAHs) and polychlorinated dibenzo-p-dioxins (PCDDs) can lead to severe adverse health effects and increase the risk of breast cancer. This review considers several mechanisms which link the tumor promoting effects of environmental pollutants with the AhR signaling pathway, contributing to the development and progression of breast cancer. We explore AhR's function in shaping the tumor microenvironment, modifying immune tolerance, and regulating cancer stemness, driving breast cancer chemoresistance and metastasis. The complexity of AhR, with evidence for both oncogenic and tumor suppressor roles is discussed. We propose that AhR functions as a "molecular bridge", linking disproportionate toxin exposure and policies which underlie environmental injustice with tumor cell behaviors which drive poor patient outcomes.
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Affiliation(s)
- Colleen Sweeney
- Department of Biochemistry and Molecular Medicine, School of Medicine, University of California Davis, Sacramento, CA, United States
| | - Gwendal Lazennec
- Centre National de la Recherche Scientifique, SYS2DIAG-ALCEN, Cap Delta, Montpellier, France
| | - Christoph F. A. Vogel
- Center for Health and the Environment, University of California Davis, Davis, CA, United States
- Department of Environmental Toxicology, University of California Davis, Davis, CA, United States
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Benoit L, Jornod F, Zgheib E, Tomkiewicz C, Koual M, Coustillet T, Barouki R, Audouze K, Vinken M, Coumoul X. Adverse outcome pathway from activation of the AhR to breast cancer-related death. ENVIRONMENT INTERNATIONAL 2022; 165:107323. [PMID: 35660951 DOI: 10.1016/j.envint.2022.107323] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 05/03/2022] [Accepted: 05/24/2022] [Indexed: 05/15/2023]
Abstract
Adverse outcome pathways (AOPs) are formalized and structured linear concepts that connect one molecular initiating event (MIE) to an adverse outcome (AO) via different key events (KE) through key event relationships (KER). They are mainly used in eco-toxicology toxicology, and regulatory health issues. AOPs must respond to specific guidelines from the Organization for Economic Co-operation and Development (OECD) to weight the evidence between each KE. Breast cancer is the deadliest cancer in women with a poor prognosis in case of metastatic breast cancer. The role of the environments in the formation of metastasis has been suggested. We hypothesized that activation of the AhR (MIE), a xenobiotic receptor, could lead to breast cancer related death (AO), through different KEs, constituting a new AOP. An artificial intelligence tool (AOP-helpfinder), which screens the available literature, was used to collect all existing scientific abstracts to build a novel AOP, using a list of key words. Four hundred and seven abstracts were found containing at least a word from our MIE list and either one word from our AO or KE list. A manual curation retained 113 pertinent articles, which were also screened using PubTator. From these analyses, an AOP was created linking the activation of the AhR to breast cancer related death through decreased apoptosis, inflammation, endothelial cell migration, angiogenesis, and invasion. These KEs promote an increased tumor growth, angiogenesis and migration which leads to breast cancer metastasis and breast cancer related death. The evidence of the proposed AOP was weighted using the tailored Bradford Hill criteria and the OECD guidelines. The confidence in our AOP was considered strong. An in vitro validation must be carried out, but our review proposes a strong relationship between AhR activation and breast cancer-related death with an innovative use of an artificial intelligence literature search.
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Affiliation(s)
- Louise Benoit
- Université Paris Cité, T3S, INSERM UMR-S 1124, 45 rue des Saints Pères, Paris, France; Assistance Publique-Hôpitaux de Paris, European Hospital Georges-Pompidou, Gynecologic and Breast Oncologic Surgery Department, Paris, France.
| | - Florence Jornod
- Université Paris Cité, T3S, INSERM UMR-S 1124, 45 rue des Saints Pères, Paris, France
| | - Elias Zgheib
- Université Paris Cité, T3S, INSERM UMR-S 1124, 45 rue des Saints Pères, Paris, France
| | - Celine Tomkiewicz
- Université Paris Cité, T3S, INSERM UMR-S 1124, 45 rue des Saints Pères, Paris, France
| | - Meriem Koual
- Université Paris Cité, T3S, INSERM UMR-S 1124, 45 rue des Saints Pères, Paris, France; Assistance Publique-Hôpitaux de Paris, European Hospital Georges-Pompidou, Gynecologic and Breast Oncologic Surgery Department, Paris, France
| | - Thibaut Coustillet
- Université Paris Cité, T3S, INSERM UMR-S 1124, 45 rue des Saints Pères, Paris, France
| | - Robert Barouki
- Université Paris Cité, T3S, INSERM UMR-S 1124, 45 rue des Saints Pères, Paris, France; Assistance Publique-Hôpitaux de Paris, European Hospital Georges-Pompidou, Gynecologic and Breast Oncologic Surgery Department, Paris, France
| | - Karine Audouze
- Université Paris Cité, T3S, INSERM UMR-S 1124, 45 rue des Saints Pères, Paris, France
| | - Mathieu Vinken
- Entity of In Vitro Toxicology and Dermato-Cosmetology, Department of Pharmaceutical and Pharmacological Sciences, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium
| | - Xavier Coumoul
- Université Paris Cité, T3S, INSERM UMR-S 1124, 45 rue des Saints Pères, Paris, France
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Carr D, Zein A, Coulombe J, Jiang T, Cabrita MA, Ward G, Daneshmand M, Sau A, Pratt MAC. Multiple roles for Bcl-3 in mammary gland branching, stromal collagen invasion, involution and tumor pathology. Breast Cancer Res 2022; 24:40. [PMID: 35681213 PMCID: PMC9185916 DOI: 10.1186/s13058-022-01536-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Accepted: 06/02/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND The Bcl-3 protein is an atypical member of the inhibitor of -κB family that has dual roles as a transcriptional repressor and a coactivator for dimers of NF-κB p50 and p52. Bcl-3 is expressed in mammary adenocarcinomas and can promote tumorigenesis and survival signaling and has a key role in tumor metastasis. In this study, we have investigated the role of Bcl-3 in the normal mammary gland and impact on tumor pathology. METHODS We utilized bcl-3-/- mice to study mammary gland structure in virgins and during gestation, lactation and early involution. Expression of involution-associated genes and proteins and putative Bcl-3 target genes was examined by qRT-PCR and immunoblot analysis. Cell autonomous branching morphogenesis and collagen I invasion properties of bcl-3-/- organoids were tested in 3D hydrogel cultures. The role of Bcl-3 in tumorigenesis and tumor pathology was also assessed using a stochastic carcinogen-induced mammary tumor model. RESULTS Bcl-3-/- mammary glands demonstrated reduced branching complexity in virgin and pregnant mice. This defect was recapitulated in vitro where significant defects in bud formation were observed in bcl-3-/- mammary organoid cultures. Bcl-3-/- organoids showed a striking defect in protrusive collective fibrillary collagen I invasion associated with reduced expression of Fzd1 and Twist2. Virgin and pregnant bcl-3-/- glands showed increased apoptosis and rapid increases in lysosomal cell death and apoptosis after forced weaning compared to WT mice. Bcl-2 and Id3 are strongly induced in WT but not bcl-3-/- glands in early involution. Tumors in WT mice were predominately adenocarcinomas with NF-κB activation, while bcl-3-/- lesions were largely squamous lacking NF-κB and with low Bcl-2 expression. CONCLUSIONS Collectively, our results demonstrate that Bcl-3 has a key function in mammary gland branching morphogenesis, in part by regulation of genes involved in extracellular matrix invasion. Markedly reduced levels of pro-survival proteins expression in bcl-3 null compared to WT glands 24 h post-weaning indicate that Bcl-3 has a role in moderating the rate of early phase involution. Lastly, a reduced incidence of bcl-3-/- mammary adenocarcinomas versus squamous lesions indicates that Bcl-3 supports the progression of epithelial but not metaplastic cancers.
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Affiliation(s)
- David Carr
- Department of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada
| | - Aiman Zein
- Department of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada
| | - Josée Coulombe
- Department of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada
| | - Tianqi Jiang
- Department of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada
| | - Miguel A Cabrita
- Department of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada
| | - Gwendoline Ward
- Department of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada
| | - Manijeh Daneshmand
- Department of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada
| | - Andrea Sau
- Department of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada
| | - M A Christine Pratt
- Department of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada.
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Guan Y, Yang YJ, Nagarajan P, Ge Y. Transcriptional and signalling regulation of skin epithelial stem cells in homeostasis, wounds and cancer. Exp Dermatol 2020; 30:529-545. [PMID: 33249665 DOI: 10.1111/exd.14247] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2020] [Revised: 10/10/2020] [Accepted: 11/13/2020] [Indexed: 02/06/2023]
Abstract
The epidermis and skin appendages are maintained by their resident epithelial stem cells, which undergo long-term self-renewal and multilineage differentiation. Upon injury, stem cells are activated to mediate re-epithelialization and restore tissue function. During this process, they often mount lineage plasticity and expand their fates in response to damage signals. Stem cell function is tightly controlled by transcription machineries and signalling transductions, many of which derail in degenerative, inflammatory and malignant dermatologic diseases. Here, by describing both well-characterized and newly emerged pathways, we discuss the transcriptional and signalling mechanisms governing skin epithelial homeostasis, wound repair and squamous cancer. Throughout, we highlight common themes underscoring epithelial stem cell plasticity and tissue-level crosstalk in the context of skin physiology and pathology.
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Affiliation(s)
- Yinglu Guan
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Youn Joo Yang
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Priyadharsini Nagarajan
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Yejing Ge
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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8
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Fomicheva M, Macara IG. Genome-wide CRISPR screen identifies noncanonical NF-κB signaling as a regulator of density-dependent proliferation. eLife 2020; 9:63603. [PMID: 33185187 PMCID: PMC7685705 DOI: 10.7554/elife.63603] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Accepted: 11/06/2020] [Indexed: 12/17/2022] Open
Abstract
Epithelial cells possess intrinsic mechanisms to maintain an appropriate cell density for normal tissue morphogenesis and homeostasis. Defects in such mechanisms likely contribute to hyperplasia and cancer initiation. To identify genes that regulate the density-dependent proliferation of murine mammary epithelial cells, we developed a fluorescence-activated cell sorting assay based on fluorescence ubiquitination cell cycle indicator, which marks different stages of the cell cycle with distinct fluorophores. Using this powerful assay, we performed a genome-wide CRISPR/Cas9 knockout screen, selecting for cells that proliferate normally at low density but continue to divide at high density. Unexpectedly, one top hit was Traf3, a negative regulator of NF-κB signaling that has never previously been linked to density-dependent proliferation. We demonstrate that loss of Traf3 specifically activates noncanonical NF-κB signaling. This in turn triggers an innate immune response and drives cell division independently of known density-dependent proliferation mechanisms, including YAP/TAZ signaling and cyclin-dependent kinase inhibitors, by blocking entry into quiescence.
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Affiliation(s)
- Maria Fomicheva
- Department of Cell and Developmental Biology Vanderbilt University School of Medicine Nashville, Nashville, United States
| | - Ian G Macara
- Department of Cell and Developmental Biology Vanderbilt University School of Medicine Nashville, Nashville, United States
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Singh MK, Singh L, Chosdol K, Pushker N, Saini N, Meel R, Bakhshi S, Sen S, Kashyap S. Differential expression of p52 and RelB proteins in the metastatic and non-metastatic groups of uveal melanoma with patient outcome. J Cancer Res Clin Oncol 2019; 145:2969-2982. [PMID: 31612319 DOI: 10.1007/s00432-019-03052-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2019] [Accepted: 10/04/2019] [Indexed: 12/20/2022]
Abstract
PURPOSE Non-canonical NFκB (NC-NFκB) pathway plays an influential role in metastasis, which promotes cancer proliferation and progression. The aim of the study was to examine the expression of NC-NFκB proteins and their correlation with clinicopathological factors associated with metastatic cases of uveal melanoma (UM) and with the patient outcome. METHOD Expression of NC-NFκB proteins (p52, RelB, and co-expression of p52/RelB) was evaluated in 75 formalin-fixed cases of uveal melanoma by immunohistochemistry. Validation of nuclear immunoreactivity was done by western blotting. Transcriptional status of NC-NFκB genes was assessed in 60 fresh tumor tissues by quantitative real-time PCR. Co-immunoprecipitation was performed to determine the presence of native p52/RelB heterodimer in UM. Prognostic relevance was determined using Cox proportional hazard and Kaplan-Meier methods. RESULTS Immunohistochemical expression of p52, RelB, and their co-expression was observed in 81%, 68.7%, 56.2% of metastatic cases, respectively, while their expression was seen only in 38%, 33% and 30% of non-metastatic cases. Loss of BAP-1 was correlated with expression of p52 and RelB proteins. Co-immunoprecipitation assay confirmed the putative interaction of p52 with RelB protein in metastatic cases of uveal melanoma. Co-expression of p52/RelB and expression of p52 protein was significantly correlated with decreased metastasis-free survival (MFS) (p = 0.004; p = 0.002) and overall survival (OS) (p = 0.004; p = 0.032), while the RelB expression only correlated with reduced MFS (p = 0.003). CONCLUSION Our data showed that non-canonical NFκB proteins were significantly higher in metastatic cases and associated with poor outcome of the patients. Furthermore, the p52 protein could be used as a potential therapeutic biomarker for metastatic cases in uveal melanoma.
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Affiliation(s)
- Mithalesh Kumar Singh
- Department of Ocular Pathology, Dr. R. P. Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India
| | - Lata Singh
- Department of Biosciences, JMI, New Delhi, India
| | | | - Neelam Pushker
- Department of Ophthalmology, Dr. R. P. Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India
- Functional Genomics Unit, Institute of Genomics and Integrative Biology, New Delhi, India
| | - Neeru Saini
- Department of Ophthalmology, Dr. R. P. Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India
- Functional Genomics Unit, Institute of Genomics and Integrative Biology, New Delhi, India
| | - Rachna Meel
- Department of Ophthalmology, Dr. R. P. Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India
- Functional Genomics Unit, Institute of Genomics and Integrative Biology, New Delhi, India
| | - Sameer Bakhshi
- Department of Medical Oncology, IRCH, AIIMS, New Delhi, India
| | - Seema Sen
- Department of Ocular Pathology, Dr. R. P. Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India
| | - Seema Kashyap
- Department of Ocular Pathology, Dr. R. P. Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India.
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10
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Costa TDF, Zhuang T, Lorent J, Turco E, Olofsson H, Masia-Balague M, Zhao M, Rabieifar P, Robertson N, Kuiper R, Sjölund J, Spiess M, Hernández-Varas P, Rabenhorst U, Roswall P, Ma R, Gong X, Hartman J, Pietras K, Adams PD, Defilippi P, Strömblad S. PAK4 suppresses RELB to prevent senescence-like growth arrest in breast cancer. Nat Commun 2019; 10:3589. [PMID: 31399573 PMCID: PMC6689091 DOI: 10.1038/s41467-019-11510-4] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2018] [Accepted: 07/17/2019] [Indexed: 01/10/2023] Open
Abstract
Overcoming cellular growth restriction, including the evasion of cellular senescence, is a hallmark of cancer. We report that PAK4 is overexpressed in all human breast cancer subtypes and associated with poor patient outcome. In mice, MMTV-PAK4 overexpression promotes spontaneous mammary cancer, while PAK4 gene depletion delays MMTV-PyMT driven tumors. Importantly, PAK4 prevents senescence-like growth arrest in breast cancer cells in vitro, in vivo and ex vivo, but is not needed in non-immortalized cells, while PAK4 overexpression in untransformed human mammary epithelial cells abrogates H-RAS-V12-induced senescence. Mechanistically, a PAK4 – RELB - C/EBPβ axis controls the senescence-like growth arrest and a PAK4 phosphorylation residue (RELB-Ser151) is critical for RELB-DNA interaction, transcriptional activity and expression of the senescence regulator C/EBPβ. These findings establish PAK4 as a promoter of breast cancer that can overcome oncogene-induced senescence and reveal a selective vulnerability of cancer to PAK4 inhibition. Oncogene induced senescence protects cells from unrestricted growth and cancer. Here, the authors show that PAK4 overrides this senescence in breast cancer cells through phosphorylation of RELB, thereby inhibiting transcription of the senescence regulator C/EBPβ.
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Affiliation(s)
- Tânia D F Costa
- Department of Biosciences and Nutrition, Karolinska Institutet, SE-141 83, Huddinge, Sweden
| | - Ting Zhuang
- Department of Biosciences and Nutrition, Karolinska Institutet, SE-141 83, Huddinge, Sweden.,Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, 453003, Henan, P.R. China
| | - Julie Lorent
- Department of Oncology-Pathology, Karolinska Institutet, SE-171 77, Solna, Sweden
| | - Emilia Turco
- Department of Genetics, Biology and Biochemistry, University of Torino, 10126, Torino, Italy
| | - Helene Olofsson
- Department of Biosciences and Nutrition, Karolinska Institutet, SE-141 83, Huddinge, Sweden
| | - Miriam Masia-Balague
- Department of Biosciences and Nutrition, Karolinska Institutet, SE-141 83, Huddinge, Sweden
| | - Miao Zhao
- Department of Biosciences and Nutrition, Karolinska Institutet, SE-141 83, Huddinge, Sweden.,Department of Immunology, Genetics and Pathology, Uppsala University, SE-752 36, Uppsala, Sweden
| | - Parisa Rabieifar
- Department of Biosciences and Nutrition, Karolinska Institutet, SE-141 83, Huddinge, Sweden
| | - Neil Robertson
- Beatson Institute for Cancer Research, Bearsden, Glasgow, G61 1BD, UK
| | - Raoul Kuiper
- Department of Laboratory Medicine, Karolinska Institutet, SE-141 57, Huddinge, Sweden
| | - Jonas Sjölund
- Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, SE-223 81, Lund, Sweden
| | - Matthias Spiess
- Department of Biosciences and Nutrition, Karolinska Institutet, SE-141 83, Huddinge, Sweden
| | - Pablo Hernández-Varas
- Department of Biosciences and Nutrition, Karolinska Institutet, SE-141 83, Huddinge, Sweden
| | - Uta Rabenhorst
- Department of Biosciences and Nutrition, Karolinska Institutet, SE-141 83, Huddinge, Sweden
| | - Pernilla Roswall
- Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-171 77, Solna, Sweden
| | - Ran Ma
- Department of Oncology-Pathology, Karolinska Institutet, SE-171 77, Solna, Sweden
| | - Xiaowei Gong
- Department of Biosciences and Nutrition, Karolinska Institutet, SE-141 83, Huddinge, Sweden
| | - Johan Hartman
- Department of Oncology-Pathology, Karolinska Institutet, SE-171 77, Solna, Sweden
| | - Kristian Pietras
- Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, SE-223 81, Lund, Sweden.,Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-171 77, Solna, Sweden
| | - Peter D Adams
- Beatson Institute for Cancer Research, Bearsden, Glasgow, G61 1BD, UK.,Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G12 8QQ, UK.,Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA, 92037, USA
| | - Paola Defilippi
- Department of Genetics, Biology and Biochemistry, University of Torino, 10126, Torino, Italy
| | - Staffan Strömblad
- Department of Biosciences and Nutrition, Karolinska Institutet, SE-141 83, Huddinge, Sweden.
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11
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Mitchell S, Hoffmann A. Substrate complex competition is a regulatory motif that allows NFκB RelA to license but not amplify NFκB RelB. Proc Natl Acad Sci U S A 2019; 116:10592-10597. [PMID: 31048505 PMCID: PMC6535030 DOI: 10.1073/pnas.1816000116] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
Signaling pathways often share molecular components, tying the activity of one pathway to the functioning of another. In the NFκB signaling system, distinct kinases mediate inflammatory and developmental signaling via RelA and RelB, respectively. Although the substrates of the developmental, so-called noncanonical, pathway are induced by inflammatory/canonical signaling, crosstalk is limited. Through dynamical systems modeling, we identified the underlying regulatory mechanism. We found that as the substrate of the noncanonical kinase NIK, the nfkb2 gene product p100, transitions from a monomer to a multimeric complex, it may compete with and inhibit p100 processing to the active p52. Although multimeric complexes of p100 (IκBδ) are known to inhibit preexisting RelA:p50 through sequestration, here we report that p100 complexes can inhibit the enzymatic formation of RelB:p52. We show that the dose-response systems properties of this complex substrate competition motif are poorly accounted for by standard Michaelis-Menten kinetics, but require more detailed mass action formulations. In sum, although tonic inflammatory signaling is required for adequate expression of the noncanonical pathway precursors, the substrate complex competition motif identified here can prevent amplification of the active RelB:p52 dimer in elevated inflammatory conditions to ensure reliable RelB-dependent developmental signaling independent of inflammatory context.
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Affiliation(s)
- Simon Mitchell
- Institute for Quantitative and Computational Biosciences, University of California, Los Angeles, CA 90095
- Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA 90095
| | - Alexander Hoffmann
- Institute for Quantitative and Computational Biosciences, University of California, Los Angeles, CA 90095;
- Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA 90095
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12
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Zeng F, Wang K, Huang R, Liu Y, Zhang Y, Hu H. RELB: A novel prognostic marker for glioblastoma as identified by population-based analysis. Oncol Lett 2019; 18:386-394. [PMID: 31289510 PMCID: PMC6540354 DOI: 10.3892/ol.2019.10296] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2018] [Accepted: 03/22/2019] [Indexed: 12/21/2022] Open
Abstract
Glioblastoma multiforme (GBM) is the most common and malignant type of glioma, with a poor prognosis for patients. The survival time of patients varies greatly due to the complexity of the human genome, which harbors diverse oncogenic drivers. In order to identify the specific driving factors, 325 glioma samples from the Chinese Glioma Genome Atlas (CGGA) database were analyzed in the present study. The level of RELB proto-oncogene, NF-κβ subunit (RELB) expression increased with the pathological grade progression of the gliomas, and higher expression levels were present in the mesenchymal subtype and isocitrate dehydrogenase 1 (IDH1) wild-type gliomas. This RELB expression pattern was identified in the CGGA database and observed in three large independent databases. In patients with GBM from the CGGA database, a higher RELB expression level was associated with a shorter survival time, a mesenchymal subtype and IDH1 wild-type gliomas. Kaplan-Meier survival analysis, survival nomograms and Cox analysis demonstrated an independent prognostic value for RELB expression. Moreover, biological function analysis indicated the association of RELB with the ‘immune response’, ‘cell activation’ and the ‘apoptotic process’. In addition, RELB expression levels exhibited a negative correlation with the levels of microRNA (miR)-139-5p and miR-139-3p. The present study identified the pathological and biological roles of RELB in glioma and revealed its independent prognostic effect. These results suggested that RELB may be used as a prognostic biomarker and potential therapeutic target in glioma.
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Affiliation(s)
- Fan Zeng
- Department of Molecular Neuropathology, Beijing Neurosurgical Institute, Capital Medical University, Beijing 100070, P.R. China.,Chinese Glioma Cooperative Group (CGCG), Beijing 100070, P.R. China
| | - Kuanyu Wang
- Department of Neurosurgery, Beijing Neurosurgical Institute, Capital Medical University, Beijing 100070, P.R. China.,Chinese Glioma Cooperative Group (CGCG), Beijing 100070, P.R. China
| | - Ruoyu Huang
- Department of Neurosurgery, Beijing Neurosurgical Institute, Capital Medical University, Beijing 100070, P.R. China.,Chinese Glioma Cooperative Group (CGCG), Beijing 100070, P.R. China
| | - Yanwei Liu
- Department of Radiotherapy, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, P.R. China.,Chinese Glioma Cooperative Group (CGCG), Beijing 100070, P.R. China
| | - Ying Zhang
- Department of Molecular Neuropathology, Beijing Neurosurgical Institute, Capital Medical University, Beijing 100070, P.R. China.,Chinese Glioma Cooperative Group (CGCG), Beijing 100070, P.R. China
| | - Huimin Hu
- Department of Molecular Neuropathology, Beijing Neurosurgical Institute, Capital Medical University, Beijing 100070, P.R. China.,Chinese Glioma Cooperative Group (CGCG), Beijing 100070, P.R. China
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13
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The impact of NF-κB signaling on pathogenesis and current treatment strategies in multiple myeloma. Blood Rev 2019; 34:56-66. [DOI: 10.1016/j.blre.2018.11.003] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Revised: 11/14/2018] [Accepted: 11/22/2018] [Indexed: 12/13/2022]
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14
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Adamska A, Falasca M. ATP-binding cassette transporters in progression and clinical outcome of pancreatic cancer: What is the way forward? World J Gastroenterol 2018; 24:3222-3238. [PMID: 30090003 PMCID: PMC6079284 DOI: 10.3748/wjg.v24.i29.3222] [Citation(s) in RCA: 78] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2018] [Revised: 05/31/2018] [Accepted: 06/27/2018] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive diseases and is characterized by high chemoresistance, leading to the lack of effective therapeutic approaches and grim prognosis. Despite increasing understanding of the mechanisms of chemoresistance in cancer and the role of ATP-binding cassette (ABC) transporters in this resistance, the therapeutic potential of their pharmacological inhibition has not been successfully exploited yet. In spite of the discovery of potent pharmacological modulators of ABC transporters, the results obtained in clinical trials have been so far disappointing, with high toxicity levels impairing their successful administration to the patients. Critically, although ABC transporters have been mostly studied for their involvement in development of multidrug resistance (MDR), in recent years the contribution of ABC transporters to cancer initiation and progression has emerged as an important area of research, the understanding of which could significantly influence the development of more specific and efficient therapies. In this review, we explore the role of ABC transporters in the development and progression of malignancies, with focus on PDAC. Their established involvement in development of MDR will be also presented. Moreover, an emerging role for ABC transporters as prognostic tools for patients' survival will be discussed, demonstrating the therapeutic potential of ABC transporters in cancer therapy.
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Affiliation(s)
- Aleksandra Adamska
- Metabolic Signalling Group, School of Pharmacy and Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth 6102, WA, Australia
| | - Marco Falasca
- Metabolic Signalling Group, School of Pharmacy and Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth 6102, WA, Australia
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15
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Noncanonical NF-κB in Cancer. Biomedicines 2018; 6:biomedicines6020066. [PMID: 29874793 PMCID: PMC6027307 DOI: 10.3390/biomedicines6020066] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2018] [Revised: 05/31/2018] [Accepted: 06/04/2018] [Indexed: 12/31/2022] Open
Abstract
The NF-κB pathway is a critical regulator of immune responses and is often dysregulated in cancer. Two NF-κB pathways have been described to mediate these responses, the canonical and the noncanonical. While understudied compared to the canonical NF-κB pathway, noncanonical NF-κB and its components have been shown to have effects, usually protumorigenic, in many different cancer types. Here, we review noncanonical NF-κB pathways and discuss its important roles in promoting cancer. We also discuss alternative NF-κB-independent functions of some the components of noncanonical NF-κB signaling. Finally, we discuss important crosstalk between canonical and noncanonical signaling, which blurs the two pathways, indicating that understanding the full picture of NF-κB regulation is critical to deciphering how this broad pathway promotes oncogenesis.
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16
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RelB intrinsically regulates the development and function of medullary thymic epithelial cells. SCIENCE CHINA-LIFE SCIENCES 2018; 61:1039-1048. [PMID: 29730722 DOI: 10.1007/s11427-017-9298-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/16/2017] [Accepted: 03/08/2018] [Indexed: 12/24/2022]
Abstract
Medullary thymic epithelial cells (mTECs) act as one of the major stromal components in the thymus for selection and maturation of both conventional T cells and non-conventional T cells. Extensive efforts have been spent to understand how mTEC development and function are regulated. Although RelB has been well accepted to be a critical transcriptional factor for mTEC development, the underlying mechanisms still remain largely unclear. In this study, by generating thymic epithelial cell specific RelB deficient mice, we found that epithelial intrinsic RelB is required for mTEC homeostatic proliferation. Mechanistically, RelB regulates the expression of genes involved in cell cycle. Functionally, lack of intrinsic RelB in thymic epithelial cells results in dramatically reduced population of mTECs and impaired development of thymic invariant natural killer T (iNKT) cells and intraepithelial lymphocyte precursors (IELPs). This study thus reveals an epithelial intrinsic role of RelB on mTEC development and function.
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17
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Xiu Y, Dong Q, Li Q, Li F, Borcherding N, Zhang W, Boyce B, Xue HH, Zhao C. Stabilization of NF-κB-Inducing Kinase Suppresses MLL-AF9-Induced Acute Myeloid Leukemia. Cell Rep 2018; 22:350-358. [PMID: 29320732 PMCID: PMC5810947 DOI: 10.1016/j.celrep.2017.12.055] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2017] [Revised: 11/02/2017] [Accepted: 12/15/2017] [Indexed: 02/08/2023] Open
Abstract
Canonical NF-κB signaling is constitutively activated in acute myeloid leukemia (AML) stem cells and is required for maintenance of the self-renewal of leukemia stem cells (LSCs). However, any potential role for NF-κB non-canonical signaling in AML has been largely overlooked. Here, we report that stabilization of NF-κB-inducing kinase (NIK) suppresses AML. Mechanistically, stabilization of NIK activates NF-κB non-canonical signaling and represses NF-κB canonical signaling. In addition, stabilization of NIK-induced activation of NF-κB non-canonical signaling upregulates Dnmt3a and downregulates Mef2c, which suppresses and promotes AML development, respectively. Importantly, by querying the connectivity MAP using up- and downregulated genes that are present exclusively in NIK-stabilized LSCs, we discovered that verteporfin has anti-AML effects, suggesting that repurposing verteporfin to target myeloid leukemia is worth testing clinically. Our data provide a scientific rationale for developing small molecules to stabilize NIK specifically in myeloid leukemias as an attractive therapeutic option.
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Affiliation(s)
- Yan Xiu
- Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
| | - Qianze Dong
- Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; Department of Pathology, China Medical University, 77 Puhe Rd., Shenbei Xinqu, Shenyang Shi, Liaoning Sheng 110122, China
| | - Qingchang Li
- Department of Pathology, China Medical University, 77 Puhe Rd., Shenbei Xinqu, Shenyang Shi, Liaoning Sheng 110122, China
| | - Fengyin Li
- Department of Microbiology and Immunology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
| | - Nick Borcherding
- Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
| | - Weizhou Zhang
- Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
| | - Brendan Boyce
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA
| | - Hai-Hui Xue
- Department of Microbiology and Immunology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
| | - Chen Zhao
- Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
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18
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Velloso FJ, Bianco AFR, Farias JO, Torres NEC, Ferruzo PYM, Anschau V, Jesus-Ferreira HC, Chang THT, Sogayar MC, Zerbini LF, Correa RG. The crossroads of breast cancer progression: insights into the modulation of major signaling pathways. Onco Targets Ther 2017; 10:5491-5524. [PMID: 29200866 PMCID: PMC5701508 DOI: 10.2147/ott.s142154] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Cancer is the disease with highest public health impact in developed countries. Particularly, breast cancer has the highest incidence in women worldwide and the fifth highest mortality in the globe, imposing a significant social and economic burden to society. The disease has a complex heterogeneous etiology, being associated with several risk factors that range from lifestyle to age and family history. Breast cancer is usually classified according to the site of tumor occurrence and gene expression profiling. Although mutations in a few key genes, such as BRCA1 and BRCA2, are associated with high breast cancer risk, the large majority of breast cancer cases are related to mutated genes of low penetrance, which are frequently altered in the whole population. Therefore, understanding the molecular basis of breast cancer, including the several deregulated genes and related pathways linked to this pathology, is essential to ensure advances in early tumor detection and prevention. In this review, we outline key cellular pathways whose deregulation has been associated with breast cancer, leading to alterations in cell proliferation, apoptosis, and the delicate hormonal balance of breast tissue cells. Therefore, here we describe some potential breast cancer-related nodes and signaling concepts linked to the disease, which can be positively translated into novel therapeutic approaches and predictive biomarkers.
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Affiliation(s)
| | | | | | | | | | - Valesca Anschau
- Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, São Paulo, Brazil
| | | | - Ted Hung-Tse Chang
- Cancer Genomics Group, International Center for Genetic Engineering and Biotechnology (ICGEB), Cape Town, South Africa
| | | | - Luiz F Zerbini
- Cancer Genomics Group, International Center for Genetic Engineering and Biotechnology (ICGEB), Cape Town, South Africa
| | - Ricardo G Correa
- Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
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19
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Begicevic RR, Falasca M. ABC Transporters in Cancer Stem Cells: Beyond Chemoresistance. Int J Mol Sci 2017; 18:E2362. [PMID: 29117122 PMCID: PMC5713331 DOI: 10.3390/ijms18112362] [Citation(s) in RCA: 257] [Impact Index Per Article: 32.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2017] [Revised: 11/02/2017] [Accepted: 11/02/2017] [Indexed: 12/19/2022] Open
Abstract
The efficacy of chemotherapy is one of the main challenges in cancer treatment and one of the major obstacles to overcome in achieving lasting remission and a definitive cure in patients with cancer is the emergence of cancer resistance. Indeed, drug resistance is ultimately accountable for poor treatment outcomes and tumour relapse. There are various molecular mechanisms involved in multidrug resistance, such as the change in the activity of membrane transporters primarily belonging to the ATP binding cassette (ABC) transporter family. In addition, it has been proposed that this common feature could be attributed to a subpopulation of slow-cycling cancer stem cells (CSCs), endowed with enhanced tumorigenic potential and multidrug resistance. CSCs are characterized by the overexpression of specific surface markers that vary in different cancer cell types. Overexpression of ABC transporters has been reported in several cancers and more predominantly in CSCs. While the major focus on the role played by ABC transporters in cancer is polarized by their involvement in chemoresistance, emerging evidence supports a more active role of these proteins, in which they release specific bioactive molecules in the extracellular milieu. This review will outline our current understanding of the role played by ABC transporters in CSCs, how their expression is regulated and how they support the malignant metabolic phenotype. To summarize, we suggest that the increased expression of ABC transporters in CSCs may have precise functional roles and provide the opportunity to target, particularly these cells, by using specific ABC transporter inhibitors.
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Affiliation(s)
- Romana-Rea Begicevic
- Metabolic Signalling Group, School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth WA 6102, Australia.
| | - Marco Falasca
- Metabolic Signalling Group, School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth WA 6102, Australia.
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20
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ATM is required for SOD2 expression and homeostasis within the mammary gland. Breast Cancer Res Treat 2017; 166:725-741. [PMID: 28849346 DOI: 10.1007/s10549-017-4424-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2017] [Accepted: 07/25/2017] [Indexed: 02/01/2023]
Abstract
PURPOSE ATM activates the NF-κB transcriptional complex in response to genotoxic and oxidative stress. The purpose of this study was to examine if the NF-κB target gene and critical antioxidant SOD2 (MnSOD) in cultured mammary epithelium is also ATM-dependent, and what phenotypes arise from deletion of ATM and SOD2 within the mammary gland. METHODS SOD2 expression was studied in human mammary epithelial cells and MCF10A using RNAi to knockdown ATM or the NF-κB subunit RelA. To study ATM and SOD2 function in mammary glands, mouse lines containing Atm or Sod2 genes containing LoxP sites were mated with mice harboring Cre recombinase under the control of the whey acidic protein promoter. Quantitative PCR was used to measure gene expression, and mammary gland structure was studied using histology. RESULTS SOD2 expression is ATM- and RelA-dependent, ATM knockdown renders cells sensitive to pro-oxidant exposure, and SOD mimetics partially rescue this sensitivity. Mice with germline deletion of Atm fail to develop mature mammary glands, but using a conditional knockout approach, we determined that Atm deletion significantly diminished the expression of Sod2. We also observed that these mice (termed AtmΔ/Δ) displayed a progressive lactation defect as judged by reduced pup growth rate, aberrant lobulo-alveolar structure, diminished milk protein gene expression, and increased apoptosis within lactating glands. This phenotype appears to be linked to dysregulated Sod2 expression as mammary gland-specific deletion of Sod2 phenocopies defects observed in AtmΔ/Δ dams. CONCLUSIONS We conclude that ATM is required to promote expression of SOD2 within the mammary epithelium, and that both ATM and SOD2 play a crucial role in mammary gland homeostasis.
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21
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Tan Z, Cheng J, Liu Q, Zhou L, Kenny J, Wang T, Lin X, Yuan J, Quinn JMW, Tickner J, Hong G, Qin A, Zhao J, Xu J. Neohesperidin suppresses osteoclast differentiation, bone resorption and ovariectomised-induced osteoporosis in mice. Mol Cell Endocrinol 2017; 439:369-378. [PMID: 27664516 DOI: 10.1016/j.mce.2016.09.026] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2016] [Revised: 09/16/2016] [Accepted: 09/21/2016] [Indexed: 12/30/2022]
Abstract
Excessive bone resorption by osteoclasts plays an important role in osteoporosis. Bone loss occurs in ovariectomised (OVX) mice in a similar manner to that in humans, so this model is suitable for evaluating potential new therapies for osteoporosis. Neohesperidin (NE) is a flavonoid compound isolated from citrus fruits. Its role in bone metabolism is unknown. In this study we found that neohesperidin inhibits osteoclast differentiation, bone resorption and the expression of osteoclast marker genes, tartrate-resistant acid phosphatase and cathepsin K. In addition, neohesperidin inhibited receptor activator of NF-κB ligand (RANKL)-induced activation of NF-κB, and the degradation of inhibitor of kappa B-alpha (IκBα). Furthermore, neohesperidin inhibited RANKL induction of nuclear factor of activated T-cells (NFAT) and calcium oscillations. In vivo treatment of ovariectomised mice with neohesperidin protected against bone loss in mice. The results suggest neohesperidin has anti-osteoclastic effects in vitro and in vivo and possesses therapeutic potential as a natural anti-catabolic treatment in osteoporosis.
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Affiliation(s)
- Zhen Tan
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Guangxi Medical University, Guangxi 530021, China; Research Centre for Regenerative Medicine, Guangxi Medical University, Guangxi 530021, China; Guangxi Key Laboratory of Regenerative Medicine, Guangxi Medical University, Guangxi 530021, China
| | - Jianwen Cheng
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Guangxi Medical University, Guangxi 530021, China; Research Centre for Regenerative Medicine, Guangxi Medical University, Guangxi 530021, China; Guangxi Key Laboratory of Regenerative Medicine, Guangxi Medical University, Guangxi 530021, China; School of Pathology and Laboratory Medicine, The University of Western Australia, Perth, WA 6009, Australia
| | - Qian Liu
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Guangxi Medical University, Guangxi 530021, China; Research Centre for Regenerative Medicine, Guangxi Medical University, Guangxi 530021, China; Guangxi Key Laboratory of Regenerative Medicine, Guangxi Medical University, Guangxi 530021, China; School of Pathology and Laboratory Medicine, The University of Western Australia, Perth, WA 6009, Australia
| | - Lin Zhou
- School of Pathology and Laboratory Medicine, The University of Western Australia, Perth, WA 6009, Australia
| | - Jacob Kenny
- School of Pathology and Laboratory Medicine, The University of Western Australia, Perth, WA 6009, Australia
| | - Tao Wang
- Research Centre for Regenerative Medicine, Guangxi Medical University, Guangxi 530021, China; Guangxi Key Laboratory of Regenerative Medicine, Guangxi Medical University, Guangxi 530021, China
| | - Xixi Lin
- Research Centre for Regenerative Medicine, Guangxi Medical University, Guangxi 530021, China; Guangxi Key Laboratory of Regenerative Medicine, Guangxi Medical University, Guangxi 530021, China
| | - Jinbo Yuan
- School of Pathology and Laboratory Medicine, The University of Western Australia, Perth, WA 6009, Australia
| | - Julian M W Quinn
- The Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
| | - Jennifer Tickner
- School of Pathology and Laboratory Medicine, The University of Western Australia, Perth, WA 6009, Australia
| | - Guoju Hong
- School of Pathology and Laboratory Medicine, The University of Western Australia, Perth, WA 6009, Australia; The National Key Discipline and the Orthopedic Laboratory, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, China
| | - An Qin
- Shanghai Key Laboratory of Orthopaedic Implant, Department of Orthopaedics, Shanghai Jiao Tong University School of Medicine, Ninth People's Hospital, Shanghai 200011, China
| | - Jinmin Zhao
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Guangxi Medical University, Guangxi 530021, China; Research Centre for Regenerative Medicine, Guangxi Medical University, Guangxi 530021, China; Guangxi Key Laboratory of Regenerative Medicine, Guangxi Medical University, Guangxi 530021, China.
| | - Jiake Xu
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Guangxi Medical University, Guangxi 530021, China; Research Centre for Regenerative Medicine, Guangxi Medical University, Guangxi 530021, China; School of Pathology and Laboratory Medicine, The University of Western Australia, Perth, WA 6009, Australia.
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22
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Lawrence CL, Baldwin AS. Non-Canonical EZH2 Transcriptionally Activates RelB in Triple Negative Breast Cancer. PLoS One 2016; 11:e0165005. [PMID: 27764181 PMCID: PMC5072726 DOI: 10.1371/journal.pone.0165005] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2016] [Accepted: 10/04/2016] [Indexed: 12/20/2022] Open
Abstract
Enhancer of zeste homology 2 (EZH2) is the methyltransferase component of the polycomb repressive complex (PRC2) which represses gene transcription via histone H3 trimethylation at lysine 23 (H3K27me3). EZH2 activity has been linked with oncogenesis where it is thought to block expression of certain tumor suppressors. Relative to a role in cancer, EZH2 functions to promote self-renewal and has been shown to be important for the tumor-initiating cell (TIC) phenotype in breast cancer. Recently a non-canonical role for EZH2 has been identified where it promotes transcriptional activation of certain genes. Here we show that EZH2, through a methyltransferase-independent mechanism, promotes the transcriptional activation of the non-canonical NF-κB subunit RelB to drive self-renewal and the TIC phenotype of triple-negative breast cancer cells.
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Affiliation(s)
- Cortney L. Lawrence
- Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina, United States of America
| | - Albert S. Baldwin
- Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina, United States of America
- * E-mail:
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23
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Baud V, Collares D. Post-Translational Modifications of RelB NF-κB Subunit and Associated Functions. Cells 2016; 5:cells5020022. [PMID: 27153093 PMCID: PMC4931671 DOI: 10.3390/cells5020022] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2016] [Revised: 04/19/2016] [Accepted: 04/26/2016] [Indexed: 01/02/2023] Open
Abstract
The family of NF-κB transcription factors plays a key role in diverse biological processes, such as inflammatory and immune responses, cell survival and tumor development. Beyond the classical NF-κB activation pathway, a second NF-κB pathway has more recently been uncovered, the so-called alternative NF-κB activation pathway. It has been shown that this pathway mainly controls the activity of RelB, a member of the NF-κB family. Post-translational modifications, such as phosphorylation, acetylation, methylation, ubiquitination and SUMOylation, have recently emerged as a strategy for the fine-tuned regulation of NF-κB. Our review discusses recent progress in the understanding of RelB regulation by post-translational modifications and the associated functions in normal and pathological conditions.
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Affiliation(s)
- Véronique Baud
- NF-κB, Differentiation and Cancer, Université Paris Descartes, Sorbonne Paris Cité, 75014 Paris, France.
| | - Davi Collares
- NF-κB, Differentiation and Cancer, Université Paris Descartes, Sorbonne Paris Cité, 75014 Paris, France
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Kochupurakkal BS, Wang ZC, Hua T, Culhane AC, Rodig SJ, Rajkovic-Molek K, Lazaro JB, Richardson AL, Biswas DK, Iglehart JD. RelA-Induced Interferon Response Negatively Regulates Proliferation. PLoS One 2015; 10:e0140243. [PMID: 26460486 PMCID: PMC4604146 DOI: 10.1371/journal.pone.0140243] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2015] [Accepted: 09/23/2015] [Indexed: 12/21/2022] Open
Abstract
Both oncogenic and tumor-suppressor activities are attributed to the Nuclear Factor kappa B (NF-kB) pathway. Moreover, NF-kB may positively or negatively regulate proliferation. The molecular determinants of these opposing roles of NF-kB are unclear. Using primary human mammary epithelial cells (HMEC) as a model, we show that increased RelA levels and consequent increase in basal transcriptional activity of RelA induces IRF1, a target gene. Induced IRF1 upregulates STAT1 and IRF7, and in consort, these factors induce the expression of interferon response genes. Activation of the interferon pathway down-regulates CDK4 and up-regulates p27 resulting in Rb hypo-phosphorylation and cell cycle arrest. Stimulation of HMEC with IFN-γ elicits similar phenotypic and molecular changes suggesting that basal activity of RelA and IFN-γ converge on IRF1 to regulate proliferation. The anti-proliferative RelA-IRF1-CDK4 signaling axis is retained in ER+/HER2- breast tumors analyzed by The Cancer Genome Atlas (TCGA). Using immuno-histochemical analysis of breast tumors, we confirm the negative correlation between RelA levels and proliferation rate in ER+/HER2- breast tumors. These findings attribute an anti-proliferative tumor-suppressor role to basal RelA activity. Inactivation of Rb, down-regulation of RelA or IRF1, or upregulation of CDK4 or IRF2 rescues the RelA-IRF1-CDK4 induced proliferation arrest in HMEC and are points of disruption in aggressive tumors. Activity of the RelA-IRF1-CDK4 axis may explain favorable response to CDK4/6 inhibition observed in patients with ER+ Rb competent tumors.
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Affiliation(s)
- Bose S. Kochupurakkal
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America
- * E-mail: (JDI); (BSK)
| | - Zhigang C. Wang
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America
| | - Tony Hua
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America
| | - Aedin C. Culhane
- Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America
| | - Scott J. Rodig
- Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, United States of America
| | | | - Jean-Bernard Lazaro
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America
| | - Andrea L. Richardson
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America
- Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, United States of America
| | - Debajit K. Biswas
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America
| | - J. Dirk Iglehart
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America
- Department of Surgery, Brigham and Women's Hospital, Boston, Massachusetts, United States of America
- * E-mail: (JDI); (BSK)
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Dang HV, Sakai T, Pham TA, Tran DH, Yorita K, Shishido Y, Fukui K. Nucling, a novel apoptosis-associated protein, controls mammary gland involution by regulating NF-κB and STAT3. J Biol Chem 2015; 290:24626-35. [PMID: 26269594 DOI: 10.1074/jbc.m115.673848] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2015] [Indexed: 11/06/2022] Open
Abstract
Postpartum mammary gland involution is the physiological process by which the lactating gland returns to its pre-pregnant state. In rodent models, the microenvironment of mammary gland involution is sufficient to induce enhanced tumor cell growth, local invasion, and metastasis. Therefore, a deeper understanding of the physiological regulation of involution may provide in-depth information on breast cancer therapy. We herein identified Nucling as an important regulator of involution of the mammary gland. A knock-out mouse model was generated and revealed that postpartum involution were impaired in mice lacking Nucling. Involution is normally associated with an increase in the activation of NF-κB and STAT3, which is required for the organized regulation of involution, and was observed in WT glands, but not in the absence of Nucling. Furthermore, the loss of Nucling led to the suppression of Calpain-1, IL-6, and C/EBPδ factors, which are known to be essential for normal involution. The number of M2 macrophages, which are crucial for epithelial cell death and adipocyte repopulation after weaning, was also reduced in Nucling-KO glands. Taken together, the results of the present study demonstrated that Nucling played an important role in mammary gland involution by regulating NF-κB and STAT3 signaling pathways.
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Affiliation(s)
- Huy Van Dang
- From The Institute for Enzyme Research, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan
| | - Takashi Sakai
- From The Institute for Enzyme Research, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan
| | - Tuan Anh Pham
- From The Institute for Enzyme Research, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan
| | - Diem Hong Tran
- From The Institute for Enzyme Research, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan
| | - Kazuko Yorita
- From The Institute for Enzyme Research, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan
| | - Yuji Shishido
- From The Institute for Enzyme Research, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan
| | - Kiyoshi Fukui
- From The Institute for Enzyme Research, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan
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26
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Labouba I, Le Page C, Communal L, Kristessen T, You X, Péant B, Barrès V, Gannon PO, Mes-Masson AM, Saad F. Potential Cross-Talk between Alternative and Classical NF-κB Pathways in Prostate Cancer Tissues as Measured by a Multi-Staining Immunofluorescence Co-Localization Assay. PLoS One 2015; 10:e0131024. [PMID: 26186215 PMCID: PMC4505937 DOI: 10.1371/journal.pone.0131024] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2015] [Accepted: 05/26/2015] [Indexed: 02/01/2023] Open
Abstract
Background While the classical NF-κB/p65 pathway is known to be involved in prostate cancer progression and is associated with poor patient outcome, the role of the NF-κB /RelB alternative protein is not well defined. Here we analyzed the activation of both NF-κB pathways in prostate cancer tissues and correlate this activation with clinical features of the disease. Methods A multiple immunofluorescence technique was employed to concomitantly and quantitatively visualize the nuclear localization of p65 and RelB in 200 paraffin embedded samples. Epithelia were defined using appropriate fluorochrome markers and the resulting immunofluorescent signals were quantified with an automated scoring system. Results The nuclear frequency of p65 was found to be significantly increased in tumor tissues as compared with normal adjacent tissue, whereas the frequency for RelB was decreased (p < 0.001, Wilcoxon test). As previously reported, p65 nuclear frequency was associated with a risk of biochemical recurrence. Although, RelB nuclear frequency alone did not predict recurrence, the presence of activated RelB reduced the risk of recurrence associated with the activation of p65. Conclusion For the first time p65/RelB co-distribution was assessed in prostate cancer tissues and suggested a negative crosstalk between the two NF-κB pathways in prostate cancer progression.
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Affiliation(s)
- Ingrid Labouba
- Institut du cancer de Montréal / Centre de recherche du Centre hospitalier de l’Université de Montréal (CRCHUM), 900 rue St-Denis, Montreal, Canada
| | - Cécile Le Page
- Institut du cancer de Montréal / Centre de recherche du Centre hospitalier de l’Université de Montréal (CRCHUM), 900 rue St-Denis, Montreal, Canada
| | - Laudine Communal
- Institut du cancer de Montréal / Centre de recherche du Centre hospitalier de l’Université de Montréal (CRCHUM), 900 rue St-Denis, Montreal, Canada
| | | | - Xiaotian You
- Institut du cancer de Montréal / Centre de recherche du Centre hospitalier de l’Université de Montréal (CRCHUM), 900 rue St-Denis, Montreal, Canada
| | - Benjamin Péant
- Institut du cancer de Montréal / Centre de recherche du Centre hospitalier de l’Université de Montréal (CRCHUM), 900 rue St-Denis, Montreal, Canada
| | - Véronique Barrès
- Institut du cancer de Montréal / Centre de recherche du Centre hospitalier de l’Université de Montréal (CRCHUM), 900 rue St-Denis, Montreal, Canada
| | - Philippe O. Gannon
- Institut du cancer de Montréal / Centre de recherche du Centre hospitalier de l’Université de Montréal (CRCHUM), 900 rue St-Denis, Montreal, Canada
| | - Anne-Marie Mes-Masson
- Institut du cancer de Montréal / Centre de recherche du Centre hospitalier de l’Université de Montréal (CRCHUM), 900 rue St-Denis, Montreal, Canada
- Department of Medicine, Université de Montréal, Montreal, Canada
| | - Fred Saad
- Institut du cancer de Montréal / Centre de recherche du Centre hospitalier de l’Université de Montréal (CRCHUM), 900 rue St-Denis, Montreal, Canada
- Division of Urology, CHUM and Department of Surgery, Université de Montréal, Montreal, Canada
- * E-mail:
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Thakar NY, Ovchinnikov DA, Hastie ML, Gorman J, Wolvetang EJ. RELB Alters Proliferation of Human Pluripotent Stem Cells via IMP3- and LIN28-Mediated Modulation of the Expression of IGF2 and Other Cell-Cycle Regulators. Stem Cells Dev 2015; 24:1888-900. [PMID: 25794352 DOI: 10.1089/scd.2014.0587] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
The molecular mechanisms that orchestrate the exit from pluripotency, cell cycle progression, and lineage-specific differentiation in human pluripotent stem cells (hPSCs) are poorly understood. RELB, a key protein in the noncanonical nuclear factor-kappaB (NFκB) signaling pathway, was previously implicated in controlling the switch between human embryonic stem cell (hESC) proliferation and differentiation. Here, we show that RELB enhances the proliferation of hESCs and human-induced pluripotent stem cells (hiPSCs) without affecting their pluripotency. We demonstrate that RELB does this by interacting with two RNA-binding proteins LIN28A and IMP3 (IGF2 mRNA-binding protein 3); further, these interactions control mRNA levels and protein expression of insulin-like growth factor 2 (IGF2) and key cell-cycle genes. Finally, after stress, these proteins co-localize in stress granules in hESCs and iPSCs. Our data identify RELB as a novel regulator of hPSC proliferation, and suggest a new function for RELB, in addition to its widely accepted role as a transcription factor, that involves recruitment of IMP3 and LIN28 to the cytosolic mRNA translation-control domains for post-transcriptional modulation of IGF2 and cell-cycle gene expression.
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Affiliation(s)
- Nilay Yogeshkumar Thakar
- 1 Stem Cell Engineering Group, Australian Institute for Bioengineering and Nanotechnology, The University of Queensland , St. Lucia, QLD, Australia
| | - Dmitry Alexander Ovchinnikov
- 1 Stem Cell Engineering Group, Australian Institute for Bioengineering and Nanotechnology, The University of Queensland , St. Lucia, QLD, Australia
| | - Marcus Lachlan Hastie
- 2 Protein Discovery Centre, QIMR Berghofer Medical Research Institute , Herston, QLD, Australia
| | - Jeffrey Gorman
- 2 Protein Discovery Centre, QIMR Berghofer Medical Research Institute , Herston, QLD, Australia
| | - Ernst Jurgen Wolvetang
- 1 Stem Cell Engineering Group, Australian Institute for Bioengineering and Nanotechnology, The University of Queensland , St. Lucia, QLD, Australia
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Wang W, Nag SA, Zhang R. Targeting the NFκB signaling pathways for breast cancer prevention and therapy. Curr Med Chem 2015; 22:264-89. [PMID: 25386819 PMCID: PMC6690202 DOI: 10.2174/0929867321666141106124315] [Citation(s) in RCA: 182] [Impact Index Per Article: 18.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2014] [Revised: 09/12/2014] [Accepted: 10/30/2014] [Indexed: 11/22/2022]
Abstract
The activation of nuclear factor-kappaB (NFκB), a proinflammatory transcription factor, is a commonly observed phenomenon in breast cancer. It facilitates the development of a hormone-independent, invasive, high-grade, and late-stage tumor phenotype. Moreover, the commonly used cancer chemotherapy and radiotherapy approaches activate NFκB, leading to the development of invasive breast cancers that show resistance to chemotherapy, radiotherapy, and endocrine therapy. Inhibition of NFκB results in an increase in the sensitivity of cancer cells to the apoptotic effects of chemotherapeutic agents and radiation and restoring hormone sensitivity, which is correlated with increased disease-free survival in patients with breast cancer. In this review article, we focus on the role of the NFκB signaling pathways in the development and progression of breast cancer and the validity of NFκB as a potential target for breast cancer prevention and therapy. We also discuss the recent findings that NFκB may have tumor suppressing activity in certain cancer types. Finally, this review also covers the state-of-the-art development of NFκB inhibitors for cancer therapy and prevention, the challenges in targeting validation, and pharmacology and toxicology evaluations of these agents from the bench to the bedside.
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Affiliation(s)
- Wei Wang
- Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA
- Cancer Biology Center, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA
| | - Subhasree A. Nag
- Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA
| | - Ruiwen Zhang
- Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA
- Cancer Biology Center, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA
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29
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Abstract
The NF-κB (nuclear factor κB) transcription factor family is a pleiotropic regulator of many cellular pathways, providing a mechanism for the cell to respond to a wide variety of stimuli and environmental challenges. It is not surprising therefore that an important component of NF-κB's function includes regulation of the cell cycle. However, this aspect of its behaviour is often overlooked and receives less attention than its ability to induce inflammatory gene expression. In the present article, we provide an updated review of the current state of our knowledge about integration of NF-κB activity with cell cycle regulation, including newly characterized direct and indirect target genes in addition to the mechanisms through which NF-κB itself can be regulated by the cell cycle.
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30
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Labouba I, Poisson A, Lafontaine J, Delvoye N, Gannon PO, Le Page C, Saad F, Mes-Masson AM. The RelB alternative NF-kappaB subunit promotes autophagy in 22Rv1 prostate cancer cells in vitro and affects mouse xenograft tumor growth in vivo. Cancer Cell Int 2014; 14:67. [PMID: 25788857 PMCID: PMC4364035 DOI: 10.1186/1475-2867-14-67] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2013] [Accepted: 05/15/2014] [Indexed: 11/17/2022] Open
Abstract
Background The involvement of NF-κB signaling in prostate cancer (PCa) has largely been established through the study of the classical p65 subunit. Nuclear localization of p65 in PCa patient tissues has been shown to correlate with biochemical recurrence, while in vitro studies have demonstrated that the classical NF-κB signaling pathway promotes PCa progression and metastatic potential. More recently, the nuclear location of RelB, a member of the alternative NF-κB signaling, has also been shown to correlate with the Gleason score. The current study aims to clarify the role of alternative NF-κB in PCa cells by exploring, in vitro and in vivo, the effects of RelB overexpression on PCa biology. Methods Using a lentivirus-expression system, we constitutively overexpressed RelB or control GFP into 22Rv1 cells and monitored alternative transcriptional NF-κB activity. In vivo, tumor growth was assessed after the injection of 22Rv1-derived cells into SCID mice. In vitro, the impact of RelB on 22Rv1 cell proliferation was evaluated in monolayer culture. The anchorage-independent cell growth of derived-22Rv1 cells was assessed by soft agar assay. Apoptosis and autophagy were evaluated by Western blot analysis in 22Rv1-derived cells cultured in suspension using poly-HEMA pre-coated dishes. Results The overexpression of RelB in 22Rv1 cells induced the constitutive activation of the alternative NF-κB pathway. In vivo, RelB expression caused a lag in the initiation of 22Rv1-induced tumors in SCID mice. In vitro, RelB stimulated the proliferation of 22Rv1 cells and reduced their ability to grow in soft agar. These observations may be reconciled by our findings that, when cultured in suspension on poly-HEMA pre-coated dishes, 22Rv1 cells expressing RelB were more susceptible to cell death, and more specifically to autophagy controlled death. Conclusions This study highlights a role of the alternative NF-κB pathway in proliferation and the controlled autophagy. Thus, the interplay of these properties may contribute to tumor survival in stress conditions while promoting PCa cells growth contributing to the overall tumorigenicity of these cells.
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Affiliation(s)
- Ingrid Labouba
- Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM)/Institut du cancer de Montréal, Montreal, Canada
| | - Alexis Poisson
- Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM)/Institut du cancer de Montréal, Montreal, Canada
| | - Julie Lafontaine
- Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM)/Institut du cancer de Montréal, Montreal, Canada
| | - Nathalie Delvoye
- Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM)/Institut du cancer de Montréal, Montreal, Canada
| | - Philippe O Gannon
- Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM)/Institut du cancer de Montréal, Montreal, Canada
| | - Cécile Le Page
- Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM)/Institut du cancer de Montréal, Montreal, Canada
| | - Fred Saad
- Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM)/Institut du cancer de Montréal, Montreal, Canada ; Division of Urology, CHUM, Université de Montréal, CHUM Notre-Dame, 1560 Sherbrooke east, Montreal, Quebec, Canada
| | - Anne-Marie Mes-Masson
- Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM)/Institut du cancer de Montréal, Montreal, Canada ; Department of Medicine, Université de Montréal, Montreal, Canada
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Ledoux AC, Sellier H, Gillies K, Iannetti A, James J, Perkins ND. NFκB regulates expression of Polo-like kinase 4. Cell Cycle 2013; 12:3052-62. [PMID: 23974100 PMCID: PMC3875679 DOI: 10.4161/cc.26086] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2013] [Revised: 08/07/2013] [Accepted: 08/07/2013] [Indexed: 01/21/2023] Open
Abstract
Activation of the NFκB signaling pathway allows the cell to respond to infection and stress and can affect many cellular processes. As a consequence, NFκB activity must be integrated with a wide variety of parallel signaling pathways. One mechanism through which NFκB can exert widespread effects is through controlling the expression of key regulatory kinases. Here we report that NFκB regulates the expression of genes required for centrosome duplication, and that Polo-like kinase 4 (PLK4) is a direct NFκB target gene. RNA interference, chromatin immunoprecipitation, and analysis of the PLK4 promoter in a luciferase reporter assay revealed that all NFκB subunits participate in its regulation. Moreover, we demonstrate that NFκB regulation of PLK4 expression is seen in multiple cell types. Significantly long-term deletion of the NFκB2 (p100/p52) subunit leads to defects in centrosome structure. This data reveals a new component of cell cycle regulation by NFκB and suggests a mechanism through which deregulated NFκB activity in cancer can lead to increased genomic instability and uncontrolled proliferation.
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Affiliation(s)
- Adeline C Ledoux
- Institute for Cell and Molecular Biosciences; Faculty of Medical Sciences; Newcastle University; Newcastle Upon Tyne, UK
| | - Hélène Sellier
- Institute for Cell and Molecular Biosciences; Faculty of Medical Sciences; Newcastle University; Newcastle Upon Tyne, UK
| | | | - Alessio Iannetti
- Institute for Cell and Molecular Biosciences; Faculty of Medical Sciences; Newcastle University; Newcastle Upon Tyne, UK
| | - John James
- College of Life Sciences; University of Dundee; Dundee, UK
| | - Neil D Perkins
- Institute for Cell and Molecular Biosciences; Faculty of Medical Sciences; Newcastle University; Newcastle Upon Tyne, UK
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32
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Abstract
RelB is one of the more unusual members of the NF-κB family. This family, arguably the best known group of transcription regulators, regulates an astonishing array of cell types and biological processes. This includes regulation of cell growth, differentiation and death by apoptosis, and the development and function of the innate and adaptive-immune system. RelB is best known for its roles in lymphoid development, DC biology, and noncanonical signaling. Within the last few years, however, surprising functions of RelB have emerged. The N-terminal leucine zipper motif of RelB, a motif unique among the NF-κB family, may associate with more diverse DNA sequences than other NF-κB members. RelB is capable of direct binding to the AhR that supports the xenobiotic-detoxifying pathway. RelB can regulate the circadian rhythm by directly binding to the BMAL partner of CLOCK. Finally, RelB also couples with bioenergy NAD(+) sensor SIRT1 to integrate acute inflammation with changes in metabolism and mitochondrial bioenergetics. In this review, we will explore these unique aspects of RelB, specifically with regard to its role in immunity.
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Affiliation(s)
- Patrick Millet
- 1.Wake Forest University Health Sciences, Wake Forest University, 1 Medical Center Blvd., Winston-Salem, NC 27157, USA.
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33
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Lindfors PH, Voutilainen M, Mikkola ML. Ectodysplasin/NF-κB signaling in embryonic mammary gland development. J Mammary Gland Biol Neoplasia 2013; 18:165-9. [PMID: 23591968 DOI: 10.1007/s10911-013-9277-5] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2013] [Accepted: 03/27/2013] [Indexed: 12/13/2022] Open
Abstract
The ectodysplasin (Eda) signaling pathway consists of a TNF-like ligand Eda, its receptor Edar, and an adaptor protein Edaradd and its activation leads to NF-κB mediated transcription. In humans, mutations in the EDA pathway genes cause hypohidrotic ectodermal dysplasia, a disorder characterized by defective formation of hair follicles, teeth, and several exocrine glands including the breast. Embryonic mammary gland development proceeds via placode, bud, bulb and sprout stages before the onset of branching morphogenesis. Studies on mouse models have linked Eda with two aspects of embryonic mammary gland morphogenesis: placode induction and ductal growth and branching. Here we summarize the current knowledge on the role of Eda/NF-κB in mammary gland development.
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Affiliation(s)
- Päivi H Lindfors
- Developmental Biology Program, Institute of Biotechnology, University of Helsinki, P.O. Box 56, 00014, Helsinki, Finland
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Transglutaminase 2 and NF-κB: an odd couple that shapes breast cancer phenotype. Breast Cancer Res Treat 2012; 137:329-36. [PMID: 23224146 DOI: 10.1007/s10549-012-2351-7] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2012] [Accepted: 11/21/2012] [Indexed: 12/17/2022]
Abstract
Owing to numerous pro-survival target genes, aberrant activation of the NF-κB transcription factor is associated with a drug-resistant phenotype and aggressive breast tumor behavior. Transglutaminase 2 (TG2), a ubiquitously expressed protein cross-linking enzyme, activates NF-κB through a non-conventional mechanism that disables the IκBα inhibitor. Our group has recently documented that the TG2 gene (termed TGM2) is a direct transcriptional target of NF-κB. These developments uncover a novel self-reinforcing molecular feedback loop where TG2 activates NF-κB and, in turn, NF-κB directly upregulates the transcription of TGM2. This manuscript reviews the literature that supports the existence of the TG2/NF-κB signaling loop, the nature of the signal transduction that activates this loop, and the phenotypic consequences stemming from the aberrant activation of this novel signaling mechanism in breast cancer.
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35
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Romagnoli M, Belguise K, Yu Z, Wang X, Landesman-Bollag E, Seldin DC, Chalbos D, Barillé-Nion S, Jézéquel P, Seldin ML, Sonenshein GE. Epithelial-to-mesenchymal transition induced by TGF-β1 is mediated by Blimp-1-dependent repression of BMP-5. Cancer Res 2012; 72:6268-78. [PMID: 23054396 DOI: 10.1158/0008-5472.can-12-2270] [Citation(s) in RCA: 75] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Induction of epithelial-to-mesenchymal transition (EMT) by TGF-β1 requires Ras signaling. We recently identified the transcriptional repressor Blimp-1 (PRDM1) as a downstream effector of the NF-κB, RelB/Bcl-2/Ras-driven pathway that promotes breast cancer cell migration. As the RelB/Blimp-1 pathway similarly required Ras signaling activation, we tested whether Blimp-1 plays a role in TGF-β1-mediated EMT. Here, TGF-β1 treatment of untransformed NMuMG mammary epithelial and MDA-MB-231 breast cancer cells was shown to induce Blimp-1 expression, which promoted an EMT signature and cell migration. TGFB1 and BLIMP1 RNA levels were correlated in patient breast tumors. BLIMP1 gene transcription was activated by TGF-β1 via a c-Raf (RAF1) to AP-1 pathway. Blimp-1 induced expression of the EMT master regulator Snail (SNAI1) via repressing BMP-5, which inhibited Snail expression upon TGF-β1 treatment. Interestingly, a similar cascade was observed during postnatal mouse mammary gland development. RelB expression was detected early in pregnancy followed progressively by Blimp-1 and then Snail; whereas, BMP-5 levels were high in nulliparous and regressing glands. Finally, lower BMP5 RNA levels were detected in patient breast tumors versus normal tissues, and correlated with cancer recurrence. Thus, the Ras effector Blimp-1 plays an essential role in TGF-β1-induced EMT via repression of BMP-5 in breast cancer.
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Affiliation(s)
- Mathilde Romagnoli
- Department of Biochemistry, Tufts University School of Medicine, Boston, MA 02111, USA
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Orabona C, Pallotta MT, Grohmann U. Different partners, opposite outcomes: a new perspective of the immunobiology of indoleamine 2,3-dioxygenase. Mol Med 2012; 18:834-42. [PMID: 22481272 DOI: 10.2119/molmed.2012.00029] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2012] [Accepted: 03/30/2012] [Indexed: 01/07/2023] Open
Abstract
Indoleamine 2,3-dioxygenase (IDO), a metabolic enzyme that catalyzes tryptophan conversion into kynurenines, is a crucial regulator of immunity. Altered IDO activity is often associated with pathology, including neoplasia and autoimmunity. IDO is highly expressed in dendritic cells (DCs) that exploit the enzyme's activity and the production of tryptophan catabolites to regulate immune responses by acting on several cell types, including T lymphocytes, of which they promote a regulatory phenotype. IDO also contains immunoreceptor tyrosine-based inhibitory motifs (ITIMs) that, once bound by distinct molecular partners, will either promote degradation or initiate signaling activity and self-maintenance of the enzyme. We here discuss how ITIM-dependent molecular events can affect the functional plasticity of IDO by modifying the protein half-life and its enzymic and nonenzymic functions.
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Affiliation(s)
- Ciriana Orabona
- Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy.
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Identification of genes regulated by the EWS/NR4A3 fusion protein in extraskeletal myxoid chondrosarcoma. Tumour Biol 2012; 33:1599-605. [DOI: 10.1007/s13277-012-0415-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2012] [Accepted: 05/03/2012] [Indexed: 10/28/2022] Open
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Ectodysplasin regulates hormone-independent mammary ductal morphogenesis via NF-κB. Proc Natl Acad Sci U S A 2012; 109:5744-9. [PMID: 22451941 DOI: 10.1073/pnas.1110627109] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Ductal growth of the mammary gland occurs in two distinct stages. The first round of branching morphogenesis occurs during embryogenesis, and the second round commences at the onset of puberty. Currently, relatively little is known about the genetic networks that control the initial phases of ductal expansion, which, unlike pubertal development, proceeds independent of hormonal input in female mice. Here we identify NF-κB downstream of the TNF-like ligand ectodysplasin (Eda) as a unique regulator of embryonic and prepubertal ductal morphogenesis. Loss of Eda, or inhibition of NF-κB, led to smaller ductal trees with fewer branches. On the other hand, overexpression of Eda caused a dramatic NF-κB-dependent phenotype in both female and male mice characterized by precocious and highly increased ductal growth and branching that correlated with enhanced cell proliferation. We have identified several putative transcriptional target genes of Eda/NF-κB, including PTHrP, Wnt10a, and Wnt10b, as well as Egf family ligands amphiregulin and epigen. We developed a mammary bud culture system that allowed us to manipulate mammary development ex vivo and found that recombinant PTHrP, Wnt3A, and Egf family ligands stimulate embryonic branching morphogenesis, suggesting that these pathways may cooperatively mediate the effects of Eda.
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Abstract
Self-renewing breast cancer stem cells are key actors in perpetuating tumour existence and in treatment resistance and relapse. The molecular pathways required for their maintenance are starting to be elucidated. Among them is the transcription factor NF-κB, which is known to play critical roles in cell survival, inflammation and immunity. Recent studies indicate that mammary epithelial NF-κB regulates the self-renewal of breast cancer stem cells in a model of Her2-dependent tumourigenesis. We will describe here the NF-κB-activating pathways that are involved in this process and in which progenitor cells this transcription factor is actually activated.
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Affiliation(s)
- Kateryna Shostak
- Interdisciplinary Cluster for Applied Genoproteomics (GIGA-Research), Unit of Medical Chemistry and GIGA-Signal Transduction, University of Liege, CHU, Sart-Tilman, 4000 Liège, Belgium
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Vogel CFA, Li W, Wu D, Miller JK, Sweeney C, Lazennec G, Fujisawa Y, Matsumura F. Interaction of aryl hydrocarbon receptor and NF-κB subunit RelB in breast cancer is associated with interleukin-8 overexpression. Arch Biochem Biophys 2011; 512:78-86. [PMID: 21640702 DOI: 10.1016/j.abb.2011.05.011] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2011] [Revised: 05/07/2011] [Accepted: 05/17/2011] [Indexed: 11/29/2022]
Abstract
The aryl hydrocarbon receptor (AhR) has been best known for its role in mediating the toxicity of dioxin. Here we show that AhR overexpression is found among estrogen receptor (ER)α-negative human breast tumors and that its overexpression is positively correlated to that of the NF-κB subunit RelB and Interleukin (IL)-8. Increased DNA binding activity of the AhR and RelB is coupled to IL-8 overexpression in primary breast cancer tissue, which was also supported by in situ hybridization. Activation of AhR in vitro by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induced IL-8 expression in MDA-MB 436 and MCF-7 cells in an AhR and RelB dependent manner. Consistently, downregulation of RelB or AhR by small interfering RNAs (siRNA) decreased the level of IL-8 but increased expression of ERα in vitro in MCF-7 cells. Our results strongly suggest that RelB and AhR have a critical role in the regulation of IL-8 and reveal a supportive role of RelB and AhR in the anti-apoptotic response in human breast cancer cells. AhR and RelB may present a novel therapeutic target for inflammatory driven breast carcinogenesis and tumor progression. Overexpression of pro-survival factors AhR and RelB may explain the process of the development of environmentally-induced type of breast cancers.
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Affiliation(s)
- Christoph Franz Adam Vogel
- Department of Environmental Toxicology, University of California Davis, One Shields Avenue, CA 95616, USA.
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Differential utilization of NF-kappaB RELA and RELB in response to extracellular versus intracellular polyIC stimulation in HT1080 cells. BMC Immunol 2011; 12:15. [PMID: 21310030 PMCID: PMC3048558 DOI: 10.1186/1471-2172-12-15] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2010] [Accepted: 02/10/2011] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Pattern recognition receptors (PRRs) for double-stranded RNA (dsRNA) are components of innate immunity that recognize the presence of viral infection and initiate efficient defense mechanisms. In addition to previously well-characterized signaling pathways that are mediated by PKR and TLR3, new intracellular dsRNA sensors, that are members of CARD and DExD/H box helicase family, have been identified. However, the molecular mechanisms involved in the signaling pathways mediated by these new dsRNA sensors have not been extensively characterized. RESULTS Here, we studied an intracellular dsRNA pathway in the human fibrosarcoma cell line HT1080, which is distinct from the TLR3-mediated extracellular dsRNA pathway. Particularly, the NF-kB subunits RELA and RELB were differentially utilized by these two dsRNA signaling pathways. In TLR3-mediated dsRNA signaling, siRNA knock-down studies suggested a limited role for RELA on regulation of interferon beta and other cytokines whereas RELB appeared to have a negative regulatory role. By contrast, intracellular dsRNA signaling was dependent on RELA, but not RELB. CONCLUSIONS Our study suggests that extracellular and intracellular dsRNA signaling pathways may utilize different NF-kB members, and particularly the differential utilization of RELB may be a key mechanism for powerful inductions of NF-kB regulated genes in the intracellular dsRNA signaling pathway.
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The Edar Subfamily in Hair and Exocrine Gland Development. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2011; 691:23-33. [DOI: 10.1007/978-1-4419-6612-4_3] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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Abstract
Two distinct nuclear factor κB (NFκB) signaling pathways have been described; the canonical pathway that mediates inflammatory responses, and the non-canonical pathway that is involved in immune cell differentiation and maturation and secondary lymphoid organogenesis. The former is dependent on the IκB kinase adaptor molecule NEMO, the latter is independent of it. Here, we review the molecular mechanisms of regulation in each signaling axis and attempt to relate the apparent regulatory logic to the physiological function. Further, we review the recent evidence for extensive cross-regulation between these two signaling axes and summarize them in a wiring diagram. These observations suggest that NEMO-dependent and -independent signaling should be viewed within the context of a single NFκB signaling system, which mediates signaling from both inflammatory and organogenic stimuli in an integrated manner. As in other regulatory biological systems, a systems approach including mathematical models that include quantitative and kinetic information will be necessary to characterize the network properties that mediate physiological function, and that may break down to cause or contribute to pathology.
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Role of oxidative stress in stem, cancer, and cancer stem cells. Cancers (Basel) 2010; 2:859-84. [PMID: 24281098 PMCID: PMC3835109 DOI: 10.3390/cancers2020859] [Citation(s) in RCA: 138] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2010] [Revised: 04/12/2010] [Accepted: 05/06/2010] [Indexed: 12/11/2022] Open
Abstract
The term ‘‘oxidative stress” refers to a cell’s state characterized by excessive production of reactive oxygen species (ROS) and oxidative stress is one of the most important regulatory mechanisms for stem, cancer, and cancer stem cells. The concept of cancer stem cells arose from observations of similarities between the self-renewal mechanism of stem cells and that of cancer stem cells, but compared to normal stem cells, they are believed to have no control over the cell number. ROS have been implicated in diverse processes in various cancers, and generally the increase of ROS in cancer cells is known to play an important role in the initiation and progression of cancer. Additionally, ROS have been considered as the most significant mutagens in stem cells; when elevated, blocking self-renewal and at the same time, serving as a signal stimulating stem cell differentiation. Several signaling pathways enhanced by oxidative stress are suggested to have important roles in tumorigenesis of cancer or cancer stem cells and the self-renewal ability of stem or cancer stem cells. It is now well established that mitochondria play a prominent role in apoptosis and increasing evidence supports that apoptosis and autophagy are physiological phenomena closely linked with oxidative stress. This review elucidates the effect and the mechanism of the oxidative stress on the regulation of stem, cancer, and cancer stem cells and focuses on the cell signaling cascades stimulated by oxidative stress and their mechanism in cancer stem cell formation, as very little is known about the redox status in cancer stem cells. Moreover, we explain the link between ROS and both of apoptosis and autophagy and the impact on cancer development and treatment. Better understanding of this intricate link may shed light on mechanisms that lead to better modes of cancer treatment.
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Jerry DJ, Dunphy KA, Hagen MJ. Estrogens, regulation of p53 and breast cancer risk: a balancing act. Cell Mol Life Sci 2010; 67:1017-23. [PMID: 20238478 PMCID: PMC11115588 DOI: 10.1007/s00018-009-0244-7] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2009] [Revised: 12/06/2009] [Accepted: 12/21/2009] [Indexed: 02/06/2023]
Abstract
The paradoxical effects of ovarian hormones in both the promotion and prevention of breast cancer have been debated for over 30 years. Genetic studies have demonstrated that ovarian hormones act through NF-kappaB to stimulate proliferation and ductal elongation, whereas the p53 tumor suppressor protein plays a central role in rendering the mammary epithelium resistant to tumorigenesis. Transcriptional profiles now suggest that ovarian hormones stimulate a constellation of genes that interact with NF-kappaB and p53 to arbitrate the competing demands for proliferation and surveillance. Genes that participate in chromatin remodeling are among the acute transcriptional responses to estrogens and progestins. These genes are proposed to initiate epigenetic programs that influence the balance between proliferation and surveillance, and render the breast epithelium resistant to tumors.
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Affiliation(s)
- D Joseph Jerry
- Paige Laboratory, Department of Veterinary and Animal Sciences, University of Massachusetts, 161 Holdsworth Way, Amherst, MA 01003-9286, USA.
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Abstract
Cyclin D1 is a key regulator of cell proliferation and its expression is subject to both transcriptional and post-transcriptional regulation. In different cellular contexts, different pathways assume a dominant role in regulating its expression, whereas their disregulation can contribute to overexpression of cyclin D1 in tumorigenesis. Here, we discuss the ability of the NF-kappaB (nuclear factor kappaB)/IKK [IkappaB (inhibitor of NF-kappaB) kinase] pathways to regulate cyclin D1 gene transcription and also consider the newly discovered role of the SNARP (SNIP1/SkIP-associated RNA processing) complex as a co-transcriptional regulator of cyclin D1 RNA stability.
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47
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Yang Z, Song L, Huang C. Gadd45 proteins as critical signal transducers linking NF-kappaB to MAPK cascades. Curr Cancer Drug Targets 2009; 9:915-30. [PMID: 20025601 PMCID: PMC3762688 DOI: 10.2174/156800909790192383] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The growth arrest and DNA damage-inducible 45 (Gadd45) proteins are a group of critical signal transducers that are involved in regulations of many cellular functions. Accumulated data indicate that all three Gadd45 proteins (i.e., Gadd45alpha, Gadd45beta, and Gadd45gamma) play essential roles in connecting an upstream sensor module, the transcription Nuclear Factor-kappaB (NF-kappaB), to a transcriptional regulating module, mitogen-activated protein kinase (MAPK). This NF-kappaB-Gadd45(s)-MAPK pathway responds to various kinds of extracellular stimuli and regulates such cell activities as growth arrest, differentiation, cell survival, and apoptosis. Defects in this pathway can also be related to oncogenesis. In the first part of this review, the functions of Gadd45 proteins, and briefly NF-kappaB and MAPK, are summarized. In the second part, the mechanisms by which Gadd45 proteins are regulated by NF-kappaB, and how they affect MAPK activation, are reviewed.
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Affiliation(s)
- Z. Yang
- Nelson Institute of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY 10987, USA
| | - L. Song
- Nelson Institute of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY 10987, USA
- Department of Cellular Immunology, Beijing Institute of Basic Medical Sciences, 27 Taiping Road, Beijing 100850, China
| | - C. Huang
- Nelson Institute of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY 10987, USA
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48
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Connelly L, Barham W, Pigg R, Saint-Jean L, Sherrill T, Cheng DS, Chodosh LA, Blackwell TS, Yull FE. Activation of nuclear factor kappa B in mammary epithelium promotes milk loss during mammary development and infection. J Cell Physiol 2009; 222:73-81. [PMID: 19746431 DOI: 10.1002/jcp.21922] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
We investigated whether nuclear factor kappa B (NF-kappaB), which exhibits a regulated pattern of activity during murine mammary gland development, plays an important role during lactation and involution, when milk production ceases and the gland undergoes apoptosis and re-modeling. We generated a doxycycline inducible transgenic mouse model to activate NF-kappaB specifically in the mammary epithelium through expression of a constitutively active form of IKK2, the upstream kinase in the classical NF-kappaB signaling cascade. We found that activation of NF-kappaB during involution resulted in a more rapid reduction in milk levels and increased cleavage of caspase-3, an indicator of apoptosis. We also found that activation of NF-kappaB during lactation with no additional involution signals had a similar effect. The observation that NF-kappaB is a key regulator of milk production led us to investigate the role of NF-kappaB during mastitis, an infection of the mammary gland in which milk loss is observed. Mammary gland injection of E. coli LPS resulted in activation of NF-kappaB and milk loss during lactation. This milk loss was decreased by selective inhibition of NF-kappaB in mammary epithelium. Together, our data reveal that activation of NF-kappaB leads to milk clearance in the lactating mammary gland. Therefore, targeting of NF-kappaB signaling may prove therapeutic during mastitis in humans and could be beneficial for the dairy industry, where such infections have a major economic impact.
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Affiliation(s)
- Linda Connelly
- Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee, USA
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49
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Mineva ND, Wang X, Yang S, Ying H, Xiao ZXJ, Holick MF, Sonenshein GE. Inhibition of RelB by 1,25-dihydroxyvitamin D3 promotes sensitivity of breast cancer cells to radiation. J Cell Physiol 2009; 220:593-9. [PMID: 19373868 DOI: 10.1002/jcp.21765] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Aberrant constitutive expression of the NF-kappaB c-Rel and RelA subunits in breast cancer cells was shown to promote their survival. Recently, we demonstrated that aggressive breast cancers constitutively express high levels of the RelB subunit, which promotes their more invasive phenotype via induction of the BCL2 gene. As these cancers are frequently resistant to therapy, here we tested the hypothesis that RelB promotes their survival. High RelB expressing Hs578T and MDA-MB-231 breast cancer cells were more resistant to gamma-radiation than MCF7 and ZR-75 cells, which express lower RelB levels. Knockdown of RelB in Hs578T led to decreased survival in response to gamma-irradiation, while conversely ectopic expression of RelB in MCF7 cells protected these cells from radiation. Similar data were obtained upon treatment of Hs578T or MCF7 cells with the chemotherapeutic agent doxorubicin. High serum levels of 25-hydroxyvitamin D are associated with decreased breast cancer risk and mortality, although, the mechanisms of its protective actions have not been fully elucidated. Treatment of Hs578T and Her-2/neu-driven NF639 cells with 1,25-dihydroxyvitamin D3 decreased RelB/RELB gene expression and levels of pro-survival targets Survivin, MnSOD and Bcl-2, while increasing their sensitivity to gamma-irradiation. Thus, RelB, which promotes survival and a more highly invasive phenotype of breast cancer cells, is a target of 1,25-dihydroxyvitamin D3, providing one mechanism for the observed protective role of 25-hydroxyvitamin D in patients with breast cancer.
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Affiliation(s)
- Nora D Mineva
- Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118, USA
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50
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Pratt MAC, Tibbo E, Robertson SJ, Jansson D, Hurst K, Perez-Iratxeta C, Lau R, Niu MY. The canonical NF-kappaB pathway is required for formation of luminal mammary neoplasias and is activated in the mammary progenitor population. Oncogene 2009; 28:2710-22. [PMID: 19483731 DOI: 10.1038/onc.2009.131] [Citation(s) in RCA: 66] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
The role of the canonical NF-kappaB pathway in mammary tumorigenesis was investigated using a transgenic (TG) mouse expressing a dominant-negative inhibitor of kappaB (IkappaBalpha(SR (S32A/S36A))) in the mammary gland under the control of the mouse mammary tumor virus promoter (MMTV). TG and control mice were subjected to a chemical carcinogenesis protocol. Hyperkeratinized squamous metaplasias (cytokeratin-6+/p63+) sometimes with a basaloid island component, were found in both TG and control mice whereas luminal (cytokeratin-19+/MUC1+) ErbB2+ papillary and adenomatous lesions developed almost exclusively in control mice. p65/RelA- and NF-kappaB DNA-binding activity were detected in mammary luminal lesions, but rarely in squamous metaplasias. Analysis of NF-kappaB family proteins and target genes using microarray data from a cohort of human mammary tumors revealed the expression of a canonical NF-kappaB pathway, but not non-canonical pathway proteins in HER2+ luminal cancers. HER2+ tumors also showed differential regulation of specific NF-kappaB target genes relative to basal and ER+ luminal cancers. Isolation of mammary cell populations enriched for stem and progenitor cell characteristics from an NF-kappaB-EGFP reporter mouse by fluorescence-activated cell sorting demonstrated that luminal progenitors contain activated NF-kappaB whereas the mammary stem cell-enriched population, does not. Together these data suggest that the canonical NF-kappaB pathway is active in normal luminal progenitor cells before transformation and is required for the formation of mammary luminal-type epithelial neoplasias.
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Affiliation(s)
- M A C Pratt
- Breast Cancer Research Lab, Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada.
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