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Hussein HA, Kassim MNI, Maulidiani M, Abas F, Abdullah MA. Cytotoxicity and 1H NMR metabolomics analyses of microalgal extracts for synergistic application with Tamoxifen on breast cancer cells with reduced toxicity against Vero cells. Heliyon 2022; 8:e09192. [PMID: 35846482 PMCID: PMC9280575 DOI: 10.1016/j.heliyon.2022.e09192] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 01/22/2022] [Accepted: 03/22/2022] [Indexed: 11/20/2022] Open
Abstract
This study evaluated the cytotoxic activity of Tamoxifen (TMX), an anti-estrogen drug, with microalgal crude extracts (MCEs) in single and synergistic application (TMX-MCEs) on MCF-7 and 4T1 breast cancer cells, and non-cancerous Vero cells. The MCEs of Nannochloropsis oculata, Tetraselmis suecica and Chlorella sp. from five different solvents (methanol, MET; ethanol, ETH; water, W; chloroform, CHL; and hexane, HEX) were developed. The TMX-MCEs-ETH and W at the 1:2 and 1:3 ratios, attained IC50 of 15.84-29.51 μg/mL against MCF-7; 13.8-31.62 μg/mL against 4T1; and 24.54-85.11 μg/mL against Vero cells. Higher late apoptosis was exhibited against MCF-7 by the TMX-N. oculata-ETH (41.15 %); and by the TMX-T. suecica-ETH (65.69 %) against 4T1 cells. The TMX-T. suecica-ETH also showed higher ADP/ATP ratios, but comparable Caspase activities to control. For Vero cells, overall apoptotic effects were lowered with synergistic application, and only early apoptosis was higher with TMX-T. suecica-ETH but at lower levels (29.84 %). The MCEs-W showed the presence of alanine, oleic acid, linoleic acid, lactic acid, and fumaric acid. Based on Principal Component Analysis (PCA), the spectral signals for polar solvents such as MET and ETH, were found in the same cluster, while the non-polar solvent CHL was with HEX, suggesting similar chemical profiles clustered for the same polarity. The CHL and HEX were more effective with N. oculata and T. suecica which were of the marine origin, while the ETH and MET were more effective with Chlorella sp., which was of the freshwater origin. The synergistic application of microalgal bioactive compounds with TMX can maintain the cytotoxicity against breast cancer cells whilst reducing the toxicity against non-cancerous Vero cells. These findings will benefit the biopharmaceutical, and functional and healthy food industries.
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Affiliation(s)
- Hanaa Ali Hussein
- Institute of Marine Biotechnology, Universiti Malaysia Terengganu, 21030 Kuala Nerus, Terengganu, Malaysia
- College of Dentistry, University of Basrah, Basrah, Iraq
| | - Murni Nur Islamiah Kassim
- Institute of Marine Biotechnology, Universiti Malaysia Terengganu, 21030 Kuala Nerus, Terengganu, Malaysia
| | - M. Maulidiani
- Faculty of Science and Marine Environment, Universiti Malaysia Terengganu, 21030 Kuala Nerus, Terengganu, Malaysia
| | - Faridah Abas
- Laboratory of Natural Products, Institute of Bioscience, Universiti Putra Malaysia, 43400 Serdang, Selangor, Malaysia
| | - Mohd Azmuddin Abdullah
- Institute of Marine Biotechnology, Universiti Malaysia Terengganu, 21030 Kuala Nerus, Terengganu, Malaysia
- SIBCo Medical and Pharmaceuticals Sdn. Bhd., No. 2, Level 5, Jalan Tengku Ampuan Zabedah, D9/D, Seksyen 9, 40000 Shah Alam, Selangor, Malaysia
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Łukasiewicz S, Czeczelewski M, Forma A, Baj J, Sitarz R, Stanisławek A. Breast Cancer-Epidemiology, Risk Factors, Classification, Prognostic Markers, and Current Treatment Strategies-An Updated Review. Cancers (Basel) 2021; 13:cancers13174287. [PMID: 34503097 PMCID: PMC8428369 DOI: 10.3390/cancers13174287] [Citation(s) in RCA: 677] [Impact Index Per Article: 169.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 08/19/2021] [Accepted: 08/23/2021] [Indexed: 02/07/2023] Open
Abstract
Simple Summary Breast cancer is the most common cancer among women. It is estimated that 2.3 million new cases of BC are diagnosed globally each year. Based on mRNA gene expression levels, BC can be divided into molecular subtypes that provide insights into new treatment strategies and patient stratifications that impact the management of BC patients. This review addresses the overview on the BC epidemiology, risk factors, classification with an emphasis on molecular types, prognostic biomarkers, as well as possible treatment modalities. Abstract Breast cancer (BC) is the most frequently diagnosed cancer in women worldwide with more than 2 million new cases in 2020. Its incidence and death rates have increased over the last three decades due to the change in risk factor profiles, better cancer registration, and cancer detection. The number of risk factors of BC is significant and includes both the modifiable factors and non-modifiable factors. Currently, about 80% of patients with BC are individuals aged >50. Survival depends on both stage and molecular subtype. Invasive BCs comprise wide spectrum tumors that show a variation concerning their clinical presentation, behavior, and morphology. Based on mRNA gene expression levels, BC can be divided into molecular subtypes (Luminal A, Luminal B, HER2-enriched, and basal-like). The molecular subtypes provide insights into new treatment strategies and patient stratifications that impact the management of BC patients. The eighth edition of TNM classification outlines a new staging system for BC that, in addition to anatomical features, acknowledges biological factors. Treatment of breast cancer is complex and involves a combination of different modalities including surgery, radiotherapy, chemotherapy, hormonal therapy, or biological therapies delivered in diverse sequences.
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Affiliation(s)
- Sergiusz Łukasiewicz
- Department of Surgical Oncology, Center of Oncology of the Lublin Region St. Jana z Dukli, 20-091 Lublin, Poland; (S.Ł.); (A.S.)
| | - Marcin Czeczelewski
- Department of Forensic Medicine, Medical University of Lublin, 20-090 Lublin, Poland; (M.C.); (A.F.)
| | - Alicja Forma
- Department of Forensic Medicine, Medical University of Lublin, 20-090 Lublin, Poland; (M.C.); (A.F.)
| | - Jacek Baj
- Department of Human Anatomy, Medical University of Lublin, 20-090 Lublin, Poland;
| | - Robert Sitarz
- Department of Surgical Oncology, Center of Oncology of the Lublin Region St. Jana z Dukli, 20-091 Lublin, Poland; (S.Ł.); (A.S.)
- Department of Human Anatomy, Medical University of Lublin, 20-090 Lublin, Poland;
- Correspondence:
| | - Andrzej Stanisławek
- Department of Surgical Oncology, Center of Oncology of the Lublin Region St. Jana z Dukli, 20-091 Lublin, Poland; (S.Ł.); (A.S.)
- Department of Oncology, Chair of Oncology and Environmental Health, Medical University of Lublin, 20-081 Lublin, Poland
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Beltran-Bless AA, Vandermeer L, Ibrahim MFK, Hutton B, Shorr R, Savard MF, Clemons M. Does the Time of Day at Which Endocrine Therapy Is Taken Affect Breast Cancer Patient Outcomes? ACTA ACUST UNITED AC 2021; 28:2523-2528. [PMID: 34287262 PMCID: PMC8293101 DOI: 10.3390/curroncol28040229] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 06/25/2021] [Accepted: 07/04/2021] [Indexed: 12/05/2022]
Abstract
Background: Non-compliance and non-persistence with endocrine therapy for breast cancer is common and usually related to treatment-induced side effects. There are anecdotal reports that simply changing the time of day when taking endocrine therapy (i.e., changing morning dosing to evening dosing or vice versa) can reduce side effects. Literature review: We conducted a literature review to evaluate whether changing the timing of tamoxifen and/or aromatase inhibitor administration impacted patient outcomes. No randomized control trials or prospective cohort studies that looked at time of day of endocrine therapy were identified through our review of literature from 1947 until August 2020. Conclusions: Given the rates of endocrine therapy non-compliance and non-persistence reported in the literature, ranging from 41–72% and 31–73%, respectively, simply changing the time of day when medications are taken could be an important strategy. We could identify no trials evaluating the effect of changes in timing of administration of endocrine therapy on breast cancer patient outcomes. Randomized control trials are clearly indicated for this simple and cost-effective intervention.
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Affiliation(s)
- Ana-Alicia Beltran-Bless
- Division of Medical Oncology, Department of Medicine, University of Ottawa and the Ottawa Hospital, Ottawa, ON K1H 8L6, Canada; (A.-A.B.-B.); (M.-F.S.)
- Ottawa Hospital Research Institute, Ottawa, ON K1Y 4E9, Canada; (L.V.); (B.H.)
| | - Lisa Vandermeer
- Ottawa Hospital Research Institute, Ottawa, ON K1Y 4E9, Canada; (L.V.); (B.H.)
| | - Mohammed F. K. Ibrahim
- Division of Clinical Sciences, Medical Oncology, Northern Ontario School of Medicine, Thunder Bay, ON P7B 5E1, Canada;
| | - Brian Hutton
- Ottawa Hospital Research Institute, Ottawa, ON K1Y 4E9, Canada; (L.V.); (B.H.)
- School of Epidemiology, Public Health and Preventive Medicine, University of Ottawa, Ottawa, ON K1G 5Z3, Canada
| | - Risa Shorr
- Ottawa Hospital, Ottawa, ON K1H 8L6, Canada;
| | - Marie-France Savard
- Division of Medical Oncology, Department of Medicine, University of Ottawa and the Ottawa Hospital, Ottawa, ON K1H 8L6, Canada; (A.-A.B.-B.); (M.-F.S.)
- Ottawa Hospital Research Institute, Ottawa, ON K1Y 4E9, Canada; (L.V.); (B.H.)
| | - Mark Clemons
- Division of Medical Oncology, Department of Medicine, University of Ottawa and the Ottawa Hospital, Ottawa, ON K1H 8L6, Canada; (A.-A.B.-B.); (M.-F.S.)
- Ottawa Hospital Research Institute, Ottawa, ON K1Y 4E9, Canada; (L.V.); (B.H.)
- Correspondence: ; Tel.: +1-613-737-7700
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Hou J, Ye X, Wang Y, Li C. Stratification of Estrogen Receptor-Negative Breast Cancer Patients by Integrating the Somatic Mutations and Transcriptomic Data. Front Genet 2021; 12:610087. [PMID: 33613637 PMCID: PMC7886807 DOI: 10.3389/fgene.2021.610087] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Accepted: 01/04/2021] [Indexed: 01/26/2023] Open
Abstract
Patients with estrogen receptor-negative breast cancer generally have a worse prognosis than estrogen receptor-positive patients. Nevertheless, a significant proportion of the estrogen receptor-negative cases have favorable outcomes. Identifying patients with a good prognosis, however, remains difficult, as recent studies are quite limited. The identification of molecular biomarkers is needed to better stratify patients. The significantly mutated genes may be potentially used as biomarkers to identify the subtype and to predict outcomes. To identify the biomarkers of receptor-negative breast cancer among the significantly mutated genes, we developed a workflow to screen significantly mutated genes associated with the estrogen receptor in breast cancer by a gene coexpression module. The similarity matrix was calculated with distance correlation to obtain gene modules through a weighted gene coexpression network analysis. The modules highly associated with the estrogen receptor, called important modules, were enriched for breast cancer-related pathways or disease. To screen significantly mutated genes, a new gene list was obtained through the overlap of the important module genes and the significantly mutated genes. The genes on this list can be used as biomarkers to predict survival of estrogen receptor-negative breast cancer patients. Furthermore, we selected six hub significantly mutated genes in the gene list which were also able to separate these patients. Our method provides a new and alternative method for integrating somatic gene mutations and expression data for patient stratification of estrogen receptor-negative breast cancers.
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Affiliation(s)
| | - Xiufen Ye
- College of Intelligent Systems Science and Engineering, Harbin Engineering University, Harbin, China
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Gooding AJ, Schiemann WP. Epithelial-Mesenchymal Transition Programs and Cancer Stem Cell Phenotypes: Mediators of Breast Cancer Therapy Resistance. Mol Cancer Res 2020; 18:1257-1270. [PMID: 32503922 DOI: 10.1158/1541-7786.mcr-20-0067] [Citation(s) in RCA: 96] [Impact Index Per Article: 19.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Revised: 04/20/2020] [Accepted: 06/02/2020] [Indexed: 12/11/2022]
Abstract
Epithelial-mesenchymal transition (EMT) programs play essential functions in normal morphogenesis and organogenesis, including that occurring during mammary gland development and glandular regeneration. Historically, EMT programs were believed to reflect a loss of epithelial gene expression signatures and morphologies that give way to those associated with mesenchymal cells and their enhanced migratory and invasive behaviors. However, accumulating evidence now paints EMT programs as representing a spectrum of phenotypic behaviors that also serve to enhance cell survival, immune tolerance, and perhaps even metastatic dormancy. Equally important, the activation of EMT programs in transformed mammary epithelial cells not only enhances their acquisition of invasive and metastatic behaviors, but also expands their generation of chemoresistant breast cancer stem cells (BCSC). Importantly, the net effect of these events results in the appearance of recurrent metastatic lesions that remain refractory to the armamentarium of chemotherapies and targeted therapeutic agents deployed against advanced stage breast cancers. Here we review the molecular and cellular mechanisms that contribute to the pathophysiology of EMT programs in human breast cancers and how these events impact their "stemness" and acquisition of chemoresistant phenotypes.
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Affiliation(s)
- Alex J Gooding
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio
| | - William P Schiemann
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio.
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Farland LV, Tamimi RM, Eliassen AH, Spiegelman D, Bertrand KA, Missmer SA. Endometriosis and mammographic density measurements in the Nurses' Health Study II. Cancer Causes Control 2016; 27:1229-37. [PMID: 27549771 DOI: 10.1007/s10552-016-0801-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2016] [Accepted: 08/15/2016] [Indexed: 01/08/2023]
Abstract
PURPOSE Endometriosis and mammographic density have been hypothesized to be influenced by sex steroid hormonal exposures in adolescence and early adulthood. We investigated the association between endometriosis and mammographic density, a consistent and independent risk factor for breast cancer. METHODS We conducted a cross-sectional analysis among 1,581 pre- and postmenopausal women not previously diagnosed with breast cancer in the Nurses' Health Study II cohort. We measured average percent mammographic density and absolute dense and non-dense breast area using a validated computer-assisted method. Multivariable linear regression was used to estimate the association between endometriosis and mammographic density among pre- and postmenopausal women separately. RESULTS Among premenopausal women, average percent mammographic density was 43.1 % among women with endometriosis (n = 91) and 40.5 % among women without endometriosis (n = 1,150). Endometriosis was not associated significantly with mammographic density among premenopausal (% difference = 2.00 percentage points 95 % CI -1.33, 5.33) or among postmenopausal women (% difference = -0.89 percentage points 95 % CI -5.10, 3.33). Among premenopausal women, there was heterogeneity by BMI at age 18 (p value = 0.003), with a suggested association among those who were lean at age 18 (BMI < 20.6 kg/m(2)) (% difference = 3.74 percentage points 95 % CI -0.29, 7.78). CONCLUSION Endometriosis was not found to be associated with overall measurements of mammographic density.
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Affiliation(s)
- Leslie V Farland
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, 677 Huntington Ave, Boston, MA, 02115, USA. .,Department of Obstetrics, Gynecology, and Reproductive Biology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
| | - Rulla M Tamimi
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, 677 Huntington Ave, Boston, MA, 02115, USA.,Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - A Heather Eliassen
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, 677 Huntington Ave, Boston, MA, 02115, USA.,Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Donna Spiegelman
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, 677 Huntington Ave, Boston, MA, 02115, USA.,Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.,Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | | | - Stacey A Missmer
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, 677 Huntington Ave, Boston, MA, 02115, USA.,Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.,Department of Obstetrics, Gynecology, and Reproductive Biology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
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Alkyne-substituted diminazene as G-quadruplex binders with anticancer activities. Eur J Med Chem 2016; 118:266-75. [DOI: 10.1016/j.ejmech.2016.04.030] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2016] [Revised: 04/11/2016] [Accepted: 04/11/2016] [Indexed: 01/18/2023]
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Lipsey CC, Harbuzariu A, Daley-Brown D, Gonzalez-Perez RR. Oncogenic role of leptin and Notch interleukin-1 leptin crosstalk outcome in cancer. World J Methodol 2016; 6:43-55. [PMID: 27019796 PMCID: PMC4804251 DOI: 10.5662/wjm.v6.i1.43] [Citation(s) in RCA: 64] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2015] [Revised: 11/11/2015] [Accepted: 03/09/2016] [Indexed: 02/06/2023] Open
Abstract
Obesity is a global pandemic characterized by high levels of body fat (adiposity) and derived-cytokines (i.e., leptin). Research shows that adiposity and leptin provide insight on the link between obesity and cancer progression. Leptin’s main function is to regulate energy balance. However, obese individuals routinely develop leptin resistance, which is the consequence of the breakdown in the signaling mechanism controlling satiety resulting in the accumulation of leptin. Therefore, leptin levels are often chronically elevated in human obesity. Elevated leptin levels are related to higher incidence, increased progression and poor prognosis of several human cancers. In addition to adipose tissue, cancer cells can also secrete leptin and overexpress leptin receptors. Leptin is known to act as a mitogen, inflammatory and pro-angiogenic factor that induces cancer cell proliferation and tumor angiogenesis. Moreover, leptin signaling induces cancer stem cells, which are involved in cancer recurrence and drug resistance. A novel and complex signaling crosstalk between leptin, Notch and interleukin-1 (IL-1) [Notch, IL-1 and leptin crosstalk outcome (NILCO)] seems to be an important driver of leptin-induced oncogenic actions. Leptin and NILCO signaling mediate the activation of cancer stem cells that can affect drug resistance. Thus, leptin and NILCO signaling are key links between obesity and cancer progression. This review presents updated data suggesting that adiposity affects cancer incidence, progression, and response to treatment. Here we show data supporting the oncogenic role of leptin in breast, endometrial, and pancreatic cancers.
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Pal A, Ganguly A, Ghosh A, Yousuf M, Rathore B, Banerjee R, Adhikari S. Bis-arylidene Oxindoles as Anti-Breast-Cancer Agents Acting via the Estrogen Receptor. ChemMedChem 2014; 9:727-32. [DOI: 10.1002/cmdc.201400003] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2014] [Indexed: 11/06/2022]
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Madeira M, Mattar A, Logullo AF, Soares FA, Gebrim LH. Estrogen receptor alpha/beta ratio and estrogen receptor beta as predictors of endocrine therapy responsiveness-a randomized neoadjuvant trial comparison between anastrozole and tamoxifen for the treatment of postmenopausal breast cancer. BMC Cancer 2013; 13:425. [PMID: 24047421 PMCID: PMC3851532 DOI: 10.1186/1471-2407-13-425] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2013] [Accepted: 09/16/2013] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND The role of estrogen receptor beta (ER-β) in breast cancer (BC) remains unclear. Some studies have suggested that ER-β may oppose the actions of estrogen receptor alpha (ER-α), and clinical evidence has indicated that the loss of ER-β expression is associated with a poor prognosis and resistance to endocrine therapy. The objective of the present study was to determine the role of ER-β and the ER-α/ER-β ratio in predicting the response to endocrine therapy and whether different regimens have any effect on ER-β expression levels. METHODS Ninety postmenopausal patients with primary BC were recruited for a short-term double-blinded randomized prospective controlled study. To determine tumor cell proliferation, we measured the expression of Ki67 in tumor biopsy samples taken before and after 26 days of treatment with anastrozole 1 mg/day (N = 25), tamoxifen 20 mg/day (N = 24) or placebo (N = 29) of 78 participants. The pre- and post-samples were placed in tissue microarray blocks and submitted for immunohistochemical assay. Biomarker statuses (ER-β, ER-α and Ki67) were obtained by comparing each immunohistochemical evaluation of the pre- and post-surgery samples using the semi-quantitative Allred's method. Statistical analyses were performed using an ANOVA and Spearman's correlation coefficient tests, with significance at p ≤ 0.05. RESULTS The frequency of ER-β expression did not change after treatment (p = 0.33). There were no significant changes in Ki67 levels in ER-β-negative cases (p = 0.45), but in the ER-β-positive cases, the anastrozole (p = 0.01) and tamoxifen groups (p = 0.04) presented a significant reduction in post-treatment Ki67 scores. There was a weak but positive correlation between the ER-α and ER-β expression levels. Only patients with an ER-α/ER-β expression ratio between 1 and 1.5 demonstrated significant differences in Ki67 levels after treatment with anastrozole (p = 0.005) and tamoxifen (p = 0.026). CONCLUSIONS Our results provide additional data that indicate that the measurement of ER-β in BC patients may help predict tamoxifen and anastrozole responsiveness in the neoadjuvant setting. These effects of hormonal treatment appear to be dependent on the ratio of ER-α/ER-β expression. TRIAL REGISTRATION Current Controlled Trials ISRCTN89801719.
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Affiliation(s)
- Marcelo Madeira
- Senology Discipline, Department of Gynecology, Federal University of Sao Paulo-UNIFESP, R, Botucatu, 740, 04023-900 Sao Paulo, SP, Brazil.
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Hofsø K, Rustøen T, Cooper BA, Bjordal K, Miaskowski C. Changes over time in occurrence, severity, and distress of common symptoms during and after radiation therapy for breast cancer. J Pain Symptom Manage 2013; 45:980-1006. [PMID: 23026547 DOI: 10.1016/j.jpainsymman.2012.06.003] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2012] [Revised: 06/04/2012] [Accepted: 06/14/2012] [Indexed: 10/27/2022]
Abstract
CONTEXT Little is known about changes over time in multiple dimensions of the symptom experience in patients with breast cancer undergoing radiation therapy (RT). OBJECTIVES This study evaluated for changes in and predictors of occurrence, severity, and distress of six common symptoms (lack of energy, worrying, difficulty sleeping, feeling drowsy, sweats, and pain) during RT for breast cancer. METHODS Patients (n = 188) completed the Memorial Symptom Assessment Scale before, during, and after the completion of RT, over a six-month period. Changes in symptom occurrence were evaluated using multilevel logistic regression analysis. Changes in severity and distress scores were evaluated using multilevel proportional odds ordinal logistic regression. The impact of five demographic and clinical characteristics (age, functional status, comorbidities, axillary lymph node dissection, and previous chemotherapy) was evaluated in these analyses. RESULTS The trajectories for occurrence, severity, and distress for the six symptoms followed similar patterns. For three of the six symptoms (lack of energy, feeling drowsy, and worrying), all three dimensions changed over time. For the other three symptoms (difficulty sleeping, sweats, and pain), no changes over time occurred for any of the symptom dimensions. The overall effect of the five covariates was to increase symptom burden across all three dimensions. CONCLUSION Findings from this study provide a more complete picture of the symptom experience of women who undergo RT for breast cancer. These findings can be used to identify patients at higher risk for more severe symptoms before, during, and after RT.
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Affiliation(s)
- Kristin Hofsø
- Centre for Shared Decision Making and Collaborative Research, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
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Chang S, Sharan SK. BRCA1 and microRNAs: emerging networks and potential therapeutic targets. Mol Cells 2012; 34:425-32. [PMID: 22936386 PMCID: PMC3887789 DOI: 10.1007/s10059-012-0118-y] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2012] [Revised: 06/08/2012] [Accepted: 06/15/2012] [Indexed: 01/28/2023] Open
Abstract
BRCA1 is a well-known tumor suppressor implicated in familial breast and ovarian cancer. Since its cloning in 1994, numerous studies have established BRCA1's role in diverse cellular and biochemical processes, such as DNA damage repair, cell cycle control, and transcriptional regulation as well as ubiquitination. In addition, a number of recent studies have functionally linked this tumor suppressor to another important cellular regulator, microRNAs, which are short (19-22 nt) RNAs that were discovered in the nematode in 1993. Soon their presence and function were validated in mammals, and since then, the role of microRNAs has been actively investigated in almost all biological processes, including cancer. In this review, we will describe recent progress in the understanding of the BRCA1 function through microRNAs and the role of microRNAs in regulating BRCA1, with emphasis on the implication of these processes on the development and progression of cancer. We will also discuss the therapeutic potential of microRNA mimics or inhibitors of microRNAs to affect BRCA1 function.
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Affiliation(s)
- Suhwan Chang
- Mouse Cancer Genetics Program, Center for Cancer Research, Frederick National Laboratory for Cancer Research, Frederick, Maryland 21702,
USA
| | - Shyam K. Sharan
- Mouse Cancer Genetics Program, Center for Cancer Research, Frederick National Laboratory for Cancer Research, Frederick, Maryland 21702,
USA
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Zhang Y, Eades G, Yao Y, Li Q, Zhou Q. Estrogen receptor α signaling regulates breast tumor-initiating cells by down-regulating miR-140 which targets the transcription factor SOX2. J Biol Chem 2012; 287:41514-22. [PMID: 23060440 DOI: 10.1074/jbc.m112.404871] [Citation(s) in RCA: 95] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Several reports have indicated that miR-140, a possible tumor suppressor microRNA (miR), is down-regulated in breast tumors compared with normal breast tissues. However, the role of miR-140 in breast tumorigenesis is unclear. We initiated studies that examined estrogen receptor α (ERα) signaling in the tissue-specific regulation of miR-140 in breast cancer. We found that estrogen stimulation of ERα-positive breast cancer cells resulted in decreased miR-140 expression. We performed promoter analyses and examined predicted ERα binding elements in the miR-140 promoter using luciferase constructs of a miR-140 promoter deletion series. Our studies revealed that ERα binds to one specific estrogen response element flanking the miR-140 promoter and consequently suppresses miR-140 transcription. We found that the stem cell self-renewal regulator SOX2 is a novel target of miR-140, and that this miR-140/SOX2 pathway critically regulates breast tumor-initiating cell survival, providing a new link between ERα signaling and breast cancer stem cell maintenance.
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Affiliation(s)
- Yongshu Zhang
- Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA
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Abstract
Much evidence now suggests that angiotensin II has roles in normal functions of the breast that may be altered or attenuated in cancer. Both angiotensin type 1 (AT1) and type 2 (AT2) receptors are present particularly in the secretory epithelium. Additionally, all the elements of a tissue renin-angiotensin system, angiotensinogen, prorenin and angiotensin-converting enzyme (ACE), are also present and distributed in different cell types in a manner suggesting a close relationship with sites of angiotensin II activity. These findings are consistent with the concept that stromal elements and myoepithelium are instrumental in maintaining normal epithelial structure and function. In disease, this system becomes disrupted, particularly in invasive carcinoma. Both AT1 and AT2 receptors are present in tumours and may be up-regulated in some. Experimentally, angiotensin II, acting via the AT1 receptor, increases tumour cell proliferation and angiogenesis, both these are inhibited by blocking its production or function. Epidemiological evidence on the effect of expression levels of ACE or the distribution of ACE or AT1 receptor variants in many types of cancer gives indirect support to these concepts. It is possible that there is a case for the therapeutic use of high doses of ACE inhibitors and AT1 receptor blockers in breast cancer, as there may be for AT2 receptor agonists, though this awaits full investigation. Attention is drawn to the possibility of blocking specific AT1-mediated intracellular signalling pathways, for example by AT1-directed antibodies, which exploit the possibility that the extracellular N-terminus of the AT1 receptor may have previously unsuspected signalling roles.
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Affiliation(s)
- Gavin P Vinson
- School of Biological and Chemical Sciences, Queen Mary University of London, London E1 4NS, UK.
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Tomao F, Spinelli G, Vici P, Pisanelli GC, Cascialli G, Frati L, Panici PB, Tomao S. Current role and safety profile of aromatase inhibitors in early breast cancer. Expert Rev Anticancer Ther 2012; 11:1253-63. [PMID: 21916579 DOI: 10.1586/era.11.96] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
The current adjuvant therapy for breast cancer is in a continous progress; standard therapeutic strategies include the use of chemotherapy, molecular targeted drugs and hormonal agents, according to well-established prognostic and predictive factors. Among the hormonal drugs, for a long period tamoxifen has been the gold standard of adjuvant therapy in postmenopausal women with hormone receptor-positive (HR+) early breast cancer. In the last years an expanding use of aromatase inhibitors occurred in this subset of patients, because the third-generation class of these agents (anastrozole, letrozole and exemestane) showed to be more effective and safe than tamoxifen and are now recommended as the preferred hormonal approach to postmenopausal hormone-sensitive patients, according to national and international guidelines. Treatment choices with these agents include the use of an aromatase inhibitor as an upfront strategy for 5 years, as a sequential approach after 2-3 years of tamoxifen, or as an extended use after the classical 5 years of tamoxifen. The improved efficacy of aromatase inhibitors over tamoxifen has been largely demonstrated in terms of better disease-free survival, reductions in the occurrence of early distant metastasis as well as improvement of overall survival. Moreover, according to the optimal duration of therapy, presently it is not known whether aromatase inhibitor therapy, as tamoxifen, should be limited to 5 years. In terms of safety profile, the side effects of aromatase inhibitors, as compared with selective estrogen receptor modulators, are different, reflecting the specific mechanism of action of these drugs. There is strong evidence that aromatase inhibitors are well tolerated, with a lower incidence of gynecological symptoms (vaginal bleeding, discharge and endometrial neoplasia), venous thromboembolic events and hot flushes than tamoxifen. On the other hand, the use of aromatase inhibitors has been associated with loss of bone density, arthralgia, myalgia, and a negative effect on lipid metabolism and cardiovascular risk. More extensive and mature studies are necessary to well establish the safety of aromatase inhibitors when given to patients with breast cancer for a long time.
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Affiliation(s)
- Federica Tomao
- Dipartimento di Scienze Ginecologico-Ostetriche e Scienze Urologiche-Università di Roma Sapienza, Rome, Italy
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16
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Walker EA, Foley JJ, Clark-Vetri R, Raffa RB. Effects of repeated administration of chemotherapeutic agents tamoxifen, methotrexate, and 5-fluorouracil on the acquisition and retention of a learned response in mice. Psychopharmacology (Berl) 2011; 217:539-48. [PMID: 21537942 PMCID: PMC3249240 DOI: 10.1007/s00213-011-2310-8] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2010] [Accepted: 04/10/2011] [Indexed: 11/28/2022]
Abstract
RATIONALE A number of cancer chemotherapeutic agents have been associated with a loss of memory in breast cancer patients although little is known of the causality of this effect. OBJECTIVES To assess the potential cognitive effects of repeated exposure to chemotherapeutic agents, we administered the selective estrogen receptor modulator tamoxifen or the antimetabolite chemotherapy, methotrexate, and 5-fluorouracil, alone and in combination to mice and tested them in a learning and memory assay. METHODS Swiss-Webster male mice were injected with saline, 32 mg/kg tamoxifen, 3.2 or 32 mg/kg methotrexate, 75 mg/kg 5-fluorouracil, 3.2 or 32 mg/kg methotrexate in combination with 75 mg/kg 5-fluorouracil once per week for 3 weeks. On days 23 and 24, mice were tested for acquisition and retention of a nose-poke response in a learning procedure called autoshaping. In addition, the acute effects of tamoxifen were assessed in additional mice in a similar procedure. RESULTS The chemotherapeutic agents alone and in combination reduced body weight relative to saline treatment over the course of 4 weeks. Repeated treatment with tamoxifen produced both acquisition and retention effects relative to the saline-treated group although acute tamoxifen was without effect except at a behaviorally toxic dose. Repeated treatment with methotrexate in combination with 5-fluorouracil produced effects on retention, but the magnitude of these changes depended on the methotrexate dose. CONCLUSIONS These data demonstrate that repeated administration of tamoxifen or certain combination of methotrexate and 5-fluorouracil may produce deficits in the acquisition or retention of learned responses which suggest potential strategies for prevention or remediation might be considered in vulnerable patient populations.
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Affiliation(s)
- Ellen A. Walker
- Department of Pharmaceutical Sciences, Temple University School of Pharmacy, 3307 North Broad Street, Philadelphia, PA 19140, USA
| | - John J. Foley
- Department of Pharmaceutical Sciences, Temple University School of Pharmacy, 3307 North Broad Street, Philadelphia, PA 19140, USA
| | - Rachel Clark-Vetri
- Department of Pharmacy Practice, Temple University School of Pharmacy, 3307 North Broad Street, Philadelphia, PA 19140, USA
| | - Robert B. Raffa
- Department of Pharmaceutical Sciences, Temple University School of Pharmacy, 3307 North Broad Street, Philadelphia, PA 19140, USA
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Verma S, Sehdev S, Joy A, Madarnas Y, Younus J, Roy JA. An updated review on the efficacy of adjuvant endocrine therapies in hormone receptor-positive early breast cancer. ACTA ACUST UNITED AC 2011; 16 Suppl 2:S1-13. [PMID: 19672416 PMCID: PMC2722048 DOI: 10.3747/co.v16i0.455] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
The third-generation aromatase inhibitors (AIS) are largely replacing tamoxifen in the adjuvant treatment of early-stage breast cancer in postmenopausal women with hormone receptor–positive tumours. To date, multiple trials have been conducted comparing tamoxifen treatment with an AI, and all have demonstrated improved disease-free survival with AI treatment. Trials have included direct 5-year comparisons between tamoxifen and an AI, switching to an AI within 5 years after initial tamoxifen treatment, or extending treatment with an AI after 5 years of completed tamoxifen treatment. Some of these trials have been completed; others are ongoing; and head-to-head trial comparisons of individual AIS are also in progress. The present article summarizes the data obtained from various clinical trials of hormonal therapy for early breast cancer. It also reviews recent data so as to shed light on the current status of these therapies. The focus is on the efficacy of treatment with an AI. Toxicity is discussed in the second article in this supplement.
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Affiliation(s)
- S Verma
- Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, ON.
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Marek CB, Peralta RM, Itinose AM, Bracht A. Influence of tamoxifen on gluconeogenesis and glycolysis in the perfused rat liver. Chem Biol Interact 2011; 193:22-33. [PMID: 21570382 DOI: 10.1016/j.cbi.2011.04.010] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2010] [Revised: 04/23/2011] [Accepted: 04/27/2011] [Indexed: 10/18/2022]
Abstract
The actions of tamoxifen, a selective estrogen receptor modulator used in chemotherapy and chemo-prevention of breast cancer, on glycolysis and gluconeogenesis were investigated in the isolated perfused rat liver. Tamoxifen inhibited gluconeogenesis from both lactate and fructose at very low concentrations (e.g., 5μM). The opposite, i.e., stimulation, was found for glycolysis from both endogenous glycogen and fructose. Oxygen uptake was unaffected, inhibited or stimulated, depending on the conditions. Stimulation occurred in both microsomes and mitochondria. Tamoxifen did not affect the most important key-enzymes of gluconeogenesis, namely, phosphoenolpyruvate carboxykinase, pyruvate carboxylase, fructose 1,6-bisphosphatase and glucose 6-phosphatase. Confirming previous observations, however, tamoxifen inhibited very strongly NADH- and succinate-oxidase of freeze-thawing disrupted mitochondria. Tamoxifen promoted the release of both lactate dehydrogenase (mainly cytosolic) and fumarase (mainly mitochondrial) into the perfusate. Tamoxifen (200μM) clearly diminished the ATP content and increased the ADP content of livers in the presence of lactate with a diminution of the ATP/ADP ratio from 1.67 to 0.79. The main causes for gluconeogenesis inhibition are probably: (a) inhibition of energy metabolism; (b) deviation of intermediates (malate and glucose 6-phosphate) for the production of NADPH required in hydroxylation and demethylation reactions; (c) deviation of glucosyl units toward glucuronidation reactions; (d) secondary inhibitory action of nitric oxide, whose production is stimulated by tamoxifen; (e) impairment of the cellular structure, especially the membrane structure. Stimulation of glycolysis is probably a compensatory phenomenon for the diminished mitochondrial ATP production. The multiple actions of tamoxifen at relatively low concentrations can represent a continuous burden to the overall hepatic functions during long treatment periods.
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Affiliation(s)
- Carla Brugin Marek
- Laboratory of Toxicology, State University of Western Paraná, Cascavel, Brazil
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19
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Santoro S, Santini M, Pepe CA, Tognetti E, Cortelazzi C, Ficarelli E, De Panfilis G. Aromatase inhibitor-induced skin adverse reactions: exemestane-related cutaneous vasculitis. J Eur Acad Dermatol Venereol 2011; 25:596-8. [DOI: 10.1111/j.1468-3083.2010.03803.x] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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Análisis de costo-efectividad en Colombia de anastrazol Vs. tamoxifeno como terapia inicial en mujeres con cáncer temprano de mama y receptor hormonal positivo. BIOMEDICA 2010. [DOI: 10.7705/biomedica.v30i1.152] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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21
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Gupta P, Sturdee DW, Palin SL, Majumder K, Fear R, Marshall T, Paterson I. Menopausal symptoms in women treated for breast cancer: the prevalence and severity of symptoms and their perceived effects on quality of life. Climacteric 2009; 9:49-58. [PMID: 16428125 DOI: 10.1080/13697130500487224] [Citation(s) in RCA: 142] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
OBJECTIVES To determine, first, the prevalence and severity of various symptoms related to estrogen deficiency in women within a few years of receiving treatment for breast cancer, second, how women perceive the effects of these symptoms on their quality of life and, third, what measures have been taken to relieve vasomotor symptoms. METHODS Two hundred women (aged 29-65 years) who had received treatment for breast cancer within the last 5 years were included in this cross-sectional survey. Information was collected about their breast cancer treatment, menopausal symptoms (Menopausal Rating Scale), the perceived effects of menopausal symptoms on their and their partner's quality of life and any treatments they were receiving for hot flushes. RESULTS All but one woman reported at least one symptom related to the menopause (95.9% vasomotor; 83.3% psychological; 89.7% somatic). Current treatment with tamoxifen or previous chemotherapy did not influence the prevalence or the severity of hot flushes. Current antidepressant treatment was, however, significantly associated with a higher prevalence and severity of most menopausal symptoms, including hot flushes and sweats (p = 0.008). The severity of hot flushes and sweats was significantly correlated with self-assessed effects on overall quality of life (r(s) = 0.47); 56.4% of the respondents believed that menopausal symptoms had affected their partner's quality of life, the strongest correlations being with severity of sexual symptoms (r(s) = 0.56) and vaginal dryness (r(s) = 0.5). Only 21% of women experiencing hot flushes were receiving any treatment for hot flushes, with most women describing no knowledge or poor knowledge of treatment options. CONCLUSIONS The majority of women receiving treatment for breast cancer report menopausal symptoms, which negatively correlate, not only with their own, but also with their partner's quality of life. Most women experiencing hot flushes are not receiving treatment due to lack of both awareness and confidence in the existing treatment options.
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Affiliation(s)
- P Gupta
- Women's Unit, Solihull Hospital, Heart of England NHS Foundation Trust, Solihull
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22
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Gene expression changes during the development of estrogen-independent and antiestrogen-resistant growth in breast cancer cell culture models. Anticancer Drugs 2009; 20:51-8. [PMID: 19343000 DOI: 10.1097/cad.0b013e32831845e1] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
We have established estrogen-independent and antiestrogen-resistant cell lines from hormone-dependent MCF-7 breast cancer cells by long-term culture in the absence of estrogen, or in the presence of antiestrogen toremifene, respectively. By using a cDNA microarray we compared gene expression profiles among estrogen-independent, antiestrogen-resistant and long-term estrogen-treated MCF-7 cells. We also determined how the expression of the differentially expressed genes has developed during the long-term culture of the cell lines. Of the screened 1176 cancer-related genes, FOSL1, TIMP1, L1CAM, GDF15, and MYBL2 were found to be differentially expressed between the cell lines. A change in FOSL1 and TIMP1 expression could be attributed to the development of antiestrogen resistance, whereas induced L1CAM expression was implicated in the development of estrogen-independent growth of the cells. Estrogen regulated genes GDF15 and L1CAM became regulated by toremifene in the later passage number of toremifene-resistant cells, which might be an indication of the developed estrogen-agonistic activity of toremifene in these cells. Our findings suggest a pattern where the hormone-responsive cancer cells, which survive E2 deprivation and/or antiestrogen treatment, first acquire necessary changes in gene expression for transition to maximal growth in the new hormonal environment. Then, after prolonged treatment with antiestrogen, the antiestrogen-resistant cells may eventually generate an E2-agonistic response to antiestrogen, probably acquiring additional growth advantage.
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23
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Abstract
Endocrine therapy plays a crucial and historically important role in the treatment ofwomen with hormone-responsive breast cancer. Tamoxifen has been the standard endocrine treatment for advanced and early-stage breast cancer for almost three decades. However, patients receiving tamoxifen may either fail to respond or develop disease recurrence following completion of therapy. The aromatase inhibitors (Als) have become the new and alternative modalities of endocrine treatment for post-menopausal women with oestrogen receptor-positive breast cancer, as a result of promising data from randomised trials in metastatic and locally advanced breast cancers. Recently, the results from several large, randomised, controlled adjuvant trials have provided further evidence that the use of Als, either as initial treatment or sequentially after tamoxifen, improves disease-free survival and, in certain patients, overall survival. With relatively short-term follow-up, the use of Als has been shown to be safe and welltolerated. Nevertheless, some detrimental adverse effects, particularly skeletal-related events or cardiovascular disease, remain important issues of concern and warrant continued monitoring and follow-up. The optimal use of Als, the appropriate timing of treatment, and the superiority of individual agents are under investigation. Use of Als in women with chemotherapy-induced amenorrhoea should be cautious due to the possibility of return of ovarian function. Cost-effectiveness and quality of life remain issues of interest since the high and ever increasing incidence of breast cancer has contributed to significant healthcare costs and patients with breast cancer following appropriate treatment are living longer but not necessarily being cured of their diseases.
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24
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Abstract
Resectable non-small-cell lung cancer (NSCLC) patients have poor prognosis, with 30-50% relapsing within 5 years. Current staging criteria do not fully capture the complexity of this disease. Survival could be improved by identification of those early-stage patients who are most likely to benefit from adjuvant therapy. Molecular classification by using mRNA expression profiles has led to multiple, poorly overlapping signatures. We hypothesized that differing statistical methodologies contribute to this lack of overlap. To test this hypothesis, we analyzed our previously published quantitative RT-PCR dataset with a semisupervised method. A 6-gene signature was identified and validated in 4 independent public microarray datasets that represent a range of tumor histologies and stages. This result demonstrated that at least 2 prognostic signatures can be derived from this single dataset. We next estimated the total number of prognostic signatures in this dataset with a 10-million-signature permutation study. Our 6-gene signature was among the top 0.02% of signatures with maximum verifiability, reaffirming its efficacy. Importantly, this analysis identified 1,789 unique signatures, implying that our dataset contains >500,000 verifiable prognostic signatures for NSCLC. This result appears to rationalize the observed lack of overlap among reported NSCLC prognostic signatures.
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25
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Wong M, Grossman J, Hahn BH, La Cava A. Cutaneous vasculitis in breast cancer treated with chemotherapy. Clin Immunol 2008; 129:3-9. [PMID: 18640073 DOI: 10.1016/j.clim.2008.07.001] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2008] [Accepted: 07/02/2008] [Indexed: 10/21/2022]
Abstract
A patient from the University of California Los Angeles Medical Center who developed cutaneous vasculitis during the course of treatment for metastatic breast cancer is presented (status: post-lumpectomy and radiation therapy). Since the onset of vasculitis occurred during the course of therapy for the neoplasm, it was difficult to differentiate between drug-induced vasculitis and paraneoplastic vasculitis. The patient had been exposed to medications including gabapentin, methimazole, trastuzumab, fulvestrant, and letrozole - which could cause endothelial cell toxicity. Drug-induced small vessel vasculitis usually attacks the skin or subcutaneous parts of the skin. In cancer therapy, there have been case reports that hormonal drugs such as estrogen receptor antagonists, aromatase inhibitors, and epidermal growth factor receptor (EGFR) inhibitors can induce cutaneous vasculitis. On the other hand, paraneoplastic syndromes manifested as cutaneous vasculitis have been documented, possibly mediated by unknown immunological mechanisms associated with the tumor such as formation of immune complexes, direct antibody-mediated effects on endothelial cells, or direct effects of tumor cells on the vascular wall. Some patients with drug-induced cutaneous vasculitis have antineutrophil cytoplasm antibodies (ANCA) directed to one or more neutrophil cytoplasm antigens - the most common being granule protein myeloperoxidase (MPO), human leukocyte elastase (HLE), cathepsin G and lactoferrin. Some patients also have antibodies against histones and antiphospholipid. Serologic testing and measurements suggest an influence of therapy on vasculitis, yet the lack of sensitivity and specificity for a biomarker in endothelial injury indicate the need to search and evaluate new markers for improved predictive value of the tests, and to provide guidance in therapy.
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Affiliation(s)
- Maida Wong
- Department of Medicine, Division of Rheumatology, University of California Los Angeles, FOCIS Center of Excellence, Los Angeles, CA 90095-1670, USA.
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26
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Salomão SR, Watanabe SES, Berezovsky A, Motono M. Multifocal electroretinography, color discrimination and ocular toxicity in tamoxifen use. Curr Eye Res 2007; 32:345-52. [PMID: 17453956 DOI: 10.1080/02713680701229638] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
PURPOSE To study prospectively retinal function, color discrimination, and ocular toxicity in women treated with standard-dosage tamoxifen for breast cancer. METHODS Thirty visually asymptomatic patients with at least 2 years of continuous tamoxifen therapy underwent multifocal electroretinography (ERG), color discrimination testing, and ophthalmic examination. The results were compared with 17 patients who were not taking tamoxifen after breast cancer surgery and to an additional age-matched group of 21 healthy women. RESULTS Multifocal electroretinogram amplitudes and latencies were comparable among the three studied groups, and individual recordings were within age norms from our own lab. In the treated group, mild diffuse color vision loss was found in two patients with normal fundi. Three other patients had ocular toxic effects, with two cases of refractile retinal crystals and one case of keratopathy. CONCLUSIONS The aspects of central retinal function that are assessed by multifocal ERG were not affected even after at least 2 years of tamoxifen use, suggesting that the multifocal ERG is not sufficiently sensitive to detect tamoxifen-associated change that might occur. Some degree of color vision loss and ocular toxic effects were found in a few cases of this cohort suggesting that women using tamoxifen should receive an eye exam at least as often as recommended for middle-aged people.
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Affiliation(s)
- Solange Rios Salomão
- Clinical Electrophysiology of Vision Laboratory, Department of Ophthalmology, Federal University of São Paulo, São Paulo, SP, Brazil.
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Highlights from: The 24th Annual Miami Breast Cancer Conference; Miami, FL; March 14–17, 2007. ACTA ACUST UNITED AC 2007; 4:137-44. [DOI: 10.1016/s1543-2912(13)60031-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Candelaria M, Hurtado-Monroy R, Vargas-Viveros P, Carrillo-Muñnoz S, Duenas-Gonzalez A. Tamoxifen-associated vasculitis in a breast cancer patient. World J Surg Oncol 2007; 5:9. [PMID: 17244373 PMCID: PMC1783853 DOI: 10.1186/1477-7819-5-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2006] [Accepted: 01/23/2007] [Indexed: 01/09/2023] Open
Abstract
Background Estrogen plays a critical role in breast cancer. Thereafter, endocrine therapy is a standard of care in patients with breast carcinoma, expressing ER or PR. Case presentation Herein we report the case of a 53-year old patient, who developed cholestasis and vasculitis during the treatment with tamoxifen. This toxicity was reversable after the removal of the drug. Thereafter she continued adjuvant treatment for breast carcinoma with anastrazole. Since tamoxifen has been widely indicated for patients with breast carcinoma, we did a literature review, looking for other cases with this type of toxicity. Conclusion This case is the third with vasculitis informed in the literature, but the first one that additionally developed cholestasis and arthritis. Although it is rare, we discuss the indication of this drug in the actual era, where aromatase inhibitors offer a better security profile.
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Affiliation(s)
- Myrna Candelaria
- Department of Hematología Oncología, Hospital Angeles del Pedregal. Mexico city, Mexico
- Division of Research. Instituto Nacional de Cancerología. Mexico city, Mexico
| | - Rafael Hurtado-Monroy
- Department of Hematología Oncología, Hospital Angeles del Pedregal. Mexico city, Mexico
| | - Pablo Vargas-Viveros
- Department of Hematología Oncología, Hospital Angeles del Pedregal. Mexico city, Mexico
| | | | - Alfonso Duenas-Gonzalez
- Division of Research. Instituto Nacional de Cancerología. Mexico city, Mexico
- Unidad de Investigaciones Biomédicas en Cáncer. Universidad Nacional Autónoma de México, Mexico
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Abstract
Tamoxifen, once the gold standard adjuvant endocrine therapy for early breast cancer, is being challenged by third-generation aromatase inhibitors (AIs) that have demonstrated improved disease-free survival in a variety of adjuvant settings for early breast cancer. Tamoxifen and AIs have different safety profiles, which should allow physicians to begin to individualize treatment based on a patient's comorbidities and risk factors. Because of its properties as a partial estrogen agonist, tamoxifen has a positive effect on serum lipids and may confer a cardioprotective benefit, as well as a beneficial effect on bone health. However, tamoxifen increases the risk for endometrial cancer and cerebrovascular/thromboembolic events. In comparison, the major side effect of AIs is increased bone loss, which may heighten the risk for osteoporotic fractures and bone pain. Because of their superior efficacy and manageable side effects, AIs are a cost-effective alternative to tamoxifen, and clinical guidelines now embrace AIs as appropriate adjuvant therapy for hormone-sensitive early breast cancer. The anticipated results of ongoing trials will provide further insights into the long-term safety and application of AI therapy in the adjuvant setting.
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30
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Reddy BS, Banerjee R. 17Beta-estradiol-associated stealth-liposomal delivery of anticancer gene to breast cancer cells. Angew Chem Int Ed Engl 2006; 44:6723-7. [PMID: 16187396 DOI: 10.1002/anie.200501793] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Affiliation(s)
- Bathula S Reddy
- Division of Lipid Science & Technology, Indian Institute of Chemical Technology, Hyderabad 500 007, India
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Fallowfield LJ, Bliss JM, Porter LS, Price MH, Snowdon CF, Jones SE, Coombes RC, Hall E. Quality of life in the intergroup exemestane study: a randomized trial of exemestane versus continued tamoxifen after 2 to 3 years of tamoxifen in postmenopausal women with primary breast cancer. J Clin Oncol 2006; 24:910-7. [PMID: 16484701 DOI: 10.1200/jco.2005.03.3654] [Citation(s) in RCA: 139] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
PURPOSE To compare and describe the quality of life (QOL) of women allocated to tamoxifen or exemestane within the Intergroup Exemestane Study (IES). PATIENTS AND METHODS Postmenopausal women with primary breast cancer who were disease free after 2 to 3 years were randomly assigned to switch from tamoxifen to exemestane or continue with tamoxifen until 5 years of treatment were completed. A subset of IES centers participated in a QOL substudy. The Functional Assessment of Cancer Therapy-Breast (FACT-B) and endocrine subscale (ES) were administered before random assignment and at predefined follow-up times. The primary end point was the FACT-B composite Trial Outcome Index (TOI). Secondary end points included total FACT-B+ES score, total ES score, and severity of individual endocrine symptoms. This analysis reports QOL up to 24 months. RESULTS Five hundred eighty-two patients from eight countries were enrolled onto the substudy. Completion and return of questionnaires was excellent, with 85% available for analysis. QOL was generally good and stable over 2 years, with no clinically meaningful differences found between groups in TOI or ES. Prevalence of severe endocrine symptoms at trial entry was high for vasomotor complaints and sexual problems, which persisted for both groups during the study. No significant differences between groups were seen for any endocrine symptoms apart from vaginal discharge, which was more pronounced with tamoxifen (P < .001). CONCLUSION The switch from tamoxifen to exemestane neither increased nor decreased endocrine symptoms present after 2 to 3 years of tamoxifen; the switch also did not initiate significant reports of new symptoms. Results indicate that the clinical benefits of exemestane over tamoxifen are achieved without significant detrimental effect on QOL.
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Affiliation(s)
- Lesley J Fallowfield
- Cancer Research UK Psychosocial Oncology Group, Brighton & Sussex Medical School, Falmer, United Kingdom.
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Hakki T, Bernhardt R. CYP17- and CYP11B-dependent steroid hydroxylases as drug development targets. Pharmacol Ther 2006; 111:27-52. [PMID: 16426683 DOI: 10.1016/j.pharmthera.2005.07.006] [Citation(s) in RCA: 64] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2005] [Accepted: 07/22/2005] [Indexed: 01/03/2023]
Abstract
Steroid hormone biosynthesis is catalyzed by the action of a series of cytochrome P450 enzymes as well as reductases. Defects in steroid hydroxylating P450s are the cause of several severe defects such as the adrenogenital syndrome (AGS), corticosterone methyl oxidase (CMO) I or II deficiencies, or pseudohermaphroditism. In contrast, overproduction of steroid hormones can be involved in breast or prostate cancer, in hypertension, and heart fibrosis. Besides inhibiting the action of the steroid hormones on the level of steroid hormone receptors by using antihormones, which often is connected with severe side effects, more recently the steroid hydroxylases themselves turned out to be promising new targets for drug development. Since the 3-dimensional structures of steroid hydroxylases are not yet available, computer models of the corresponding CYPs may help to develop new inhibitors of these enzymes. During the past years, the necessary test systems have been developed and new compounds have been synthesized, which displayed selective and specific inhibition of CYP17, CYP11B2, and CYP11B1. With some of these potential new drugs, clinical trials are under way. It can be expected that in the near future some of these compounds will contribute to our arsenal of new and selective drugs.
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Affiliation(s)
- Tarek Hakki
- Institute of Biochemistry, P.O. Box 151150, Saarland University, D-66041 Saarbrücken, Germany
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33
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Abstract
The review summarizes the outcomes of several landmark trials involving aromatase inhibitors that helped formulate current therapeutic approaches recommended by the American Society of Clinical Oncology for breast carcinoma treatment.
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Affiliation(s)
- William Gradishar
- Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
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34
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Chen JQ, Contreras RG, Wang R, Fernandez SV, Shoshani L, Russo IH, Cereijido M, Russo J. Sodium/potasium ATPase (Na+, K+-ATPase) and ouabain/related cardiac glycosides: a new paradigm for development of anti- breast cancer drugs? Breast Cancer Res Treat 2005; 96:1-15. [PMID: 16322895 DOI: 10.1007/s10549-005-9053-3] [Citation(s) in RCA: 76] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2005] [Accepted: 08/11/2005] [Indexed: 11/30/2022]
Abstract
Prolonged exposure to 17beta-estradiol (E2) is a key etiological factor for human breast cancer. The biological effects and carcinogenic effects of E2 are mediated via estrogen receptors (ERs), ERalpha and ERbeta. Anti-estrogens, e.g. tamoxifen, and aromatase inhibitors have been used to treat ER-positive breast cancer. While anti-estrogen therapy is initially successful, a major problem is that most tumors develop resistance and the disease ultimately progresses, pointing to the need of developing alternative drugs targeting to other critical targets in breast cancer cells. We have identified that Na+, K+-ATPase, a plasma membrane ion pump, has unique/valuable properties that could be used as a potentially important target for breast cancer treatment: (a) it is a key player of cell adhesion and is involved in cancer progression; (b) it serves as a versatile signal transducer and is a target for a number of hormones including estrogens and (d) its aberrant expression and activity are implicated in the development and progression of breast cancer. There are several lines of evidence indicating that ouabain and related digitalis (the potent inhibitors of Na+, K+-ATPase) possess potent anti-breast cancer activity. While it is not clear how the suggested anti-cancer activity of these drugs work, several observations point to ouabain and digitalis as being potential ER antagonists. We critically reviewed many lines of evidence and postulated a novel concept that Na+, K+-ATPase in combination with ERs could be important targets of anti-breast cancer drugs. Modulators, e.g. ouabain and related digitalis could be useful to develop valuable anti-breast cancer drugs as both Na+, K+-ATPase inhibitors and ER antagonists.
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Affiliation(s)
- Jin-Qiang Chen
- Breast Cancer Research Laboratory, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
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35
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Trafalis DTP, Geromichalos GD, Koukoulitsa C, Papageorgiou A, Karamanakos P, Camoutsis C. Lactandrate: a D-homo-aza-androsterone alkylator in the treatment of breast cancer. Breast Cancer Res Treat 2005; 97:17-31. [PMID: 16319980 DOI: 10.1007/s10549-005-9083-x] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2005] [Accepted: 09/16/2005] [Indexed: 10/25/2022]
Abstract
The sensitivity of breast neoplasms to hormonal control provides the basis of novel investigational treatments with steroidal alkylators. An androsterone D-lactam steroidal ester, the 3beta-hydroxy-13alpha-amino-13,17-seco- 5alpha-androstan-17-oic-13,17-lactam, p-bis(2-chloroethyl)amino phenyl acetate (lactandrate) was synthesized and tested for antitumor activity against six human breast cancer cell lines in vitro and against two murine and one xenograft mammary tumors in vivo. A docking study on the binding interactions of lactandrate with the ligand-binding domain (LBD) of estrogen receptor-alpha (ERalpha) was inquired. In vitro testing of lactandrate cytostatic and cytotoxic activity was performed on T47D, MCF7, MDA-MB-231, BT-549, Hs578T, MDA-MB-435 breast adenocarcinoma human cell lines. In vivo testing was performed on two murine mammary tumors, the MXT tumor and CD8F1 adenocarcinoma, as well as on human mammary carcinoma MX-1 xenograft. Molecular modeling techniques were adopted to predict a possible location and interaction mode of the molecule into LBD. Lactandrate induced significantly high antitumor effect against all tested in vitro and in vivo models. The cell lines with positive ER expression found to be significantly more sensitive to lactandrate. Moreover, lactandrate found to be positioned inside the binding cavity with its steroidal moiety, whilst the alkylating moiety protrudes out of receptor's pocket. Lactandrate produced important anticancer activity on breast cancer in vitro and in vivo. Some correlation between ER and lactandrate effect was demonstrated. Docking studies provide the basis for the structure-based design of improved steroidal alkylating esters for the treatment of estrogen-related cancers.
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Affiliation(s)
- Dimitrios T P Trafalis
- Laboratory of Medicinal Chemistry, Faculty of Pharmacy, University of Patras, Patras, Greece.
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36
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Reddy BS, Banerjee R. 17β-Estradiol-Associated Stealth-Liposomal Delivery of Anticancer Gene to Breast Cancer Cells. Angew Chem Int Ed Engl 2005. [DOI: 10.1002/ange.200501793] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
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37
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Fleming CD, Bencharit S, Edwards CC, Hyatt JL, Tsurkan L, Bai F, Fraga C, Morton CL, Howard-Williams EL, Potter PM, Redinbo MR. Structural insights into drug processing by human carboxylesterase 1: tamoxifen, mevastatin, and inhibition by benzil. J Mol Biol 2005; 352:165-77. [PMID: 16081098 DOI: 10.1016/j.jmb.2005.07.016] [Citation(s) in RCA: 106] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2005] [Revised: 07/05/2005] [Accepted: 07/06/2005] [Indexed: 11/24/2022]
Abstract
Human carboxylesterase 1 (hCE1) exhibits broad substrate specificity and is involved in xenobiotic processing and endobiotic metabolism. We present and analyze crystal structures of hCE1 in complexes with the cholesterol-lowering drug mevastatin, the breast cancer drug tamoxifen, the fatty acyl ethyl ester (FAEE) analogue ethyl acetate, and the novel hCE1 inhibitor benzil. We find that mevastatin does not appear to be a substrate for hCE1, and instead acts as a partially non-competitive inhibitor of the enzyme. Similarly, we show that tamoxifen is a low micromolar, partially non-competitive inhibitor of hCE1. Further, we describe the structural basis for the inhibition of hCE1 by the nanomolar-affinity dione benzil, which acts by forming both covalent and non-covalent complexes with the enzyme. Our results provide detailed insights into the catalytic and non-catalytic processing of small molecules by hCE1, and suggest that the efficacy of clinical drugs may be modulated by targeted hCE1 inhibitors.
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Affiliation(s)
- Christopher D Fleming
- Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
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38
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Antoch MP, Kondratov RV, Takahashi JS. Circadian clock genes as modulators of sensitivity to genotoxic stress. Cell Cycle 2005; 4:901-7. [PMID: 15917646 PMCID: PMC3774065 DOI: 10.4161/cc.4.7.1792] [Citation(s) in RCA: 58] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
A broad variety of organisms display circadian rhythms (i.e., oscillations with 24-hr periodicities) in many aspects of their behavior, physiology and metabolism. These rhythms are under genetic control and are generated endogenously at the cellular level. In mammals, the core molecular mechanism of the oscillator consists of two transcriptional activators, CLOCK and BMAL1, and their transcriptional targets, CRYPTOCHROMES (CRYS) and PERIODS (PERS). The CRY and PER proteins function as negative regulators of CLOCK/BMAL1 activity, thus forming the major circadian autoregulatory feedback loop. It is believed that the circadian clock system regulates daily variations in output physiology and metabolism through periodic activation/repression of the set of clock-controlled genes that are involved in various metabolic pathways. Importantly, circadian-controlled pathways include those that determine in vivo responses to genotoxic stress. By using circadian mutant mice deficient in different components of the molecular clock system, we have established genetic models that correlate with the two opposite extremes of circadian cycle as reflected by the activity of the CLOCK/BMAL1 transactivation complex. Comparison of the in vivo responses of these mutants to the chemotherapeutic drug, cyclophosphamide (CY), has established a direct correlation between drug toxicity and the functional status of the CLOCK/BMAL1 transcriptional complex. We have also demonstrated that CLOCK/BMAL1 modulates sensitivity to drug-induced toxicity by controlling B cell responses to active CY metabolites. These results suggest that the sensitivity of cells to genotoxic stress induced by anticancer therapy may be modulated by CLOCK/BMAL1 transcriptional activity. Further elucidation of the molecular mechanisms of circadian control as well as identification of specific pharmacological modulators of CLOCK/BMAL1 activity are likely to lead to the development of new anti-cancer treatment schedules with increased therapeutic index and reduced morbidity.
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Affiliation(s)
- Marina P Antoch
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
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