• Cell proliferation
• Central nervous system
• Epidermal growth factor
• Insulin-like growth factor-1
• Retina
• Signaling pathway

Tyrosine kinase inhibitors (TKIs) are frequently used in combined therapy to enhance treatment efficacy and overcome drug resistance. The present study analyzed the effects of three inhibitors, sunitinib, gefitinib, and lapatinib, combined with iron-chelating agents, di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT) or di-2-pyridylketone-4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC). Simultaneous administration of the drugs consistently resulted in synergistic and/or additive activities against the cell lines derived from the most frequent types of pediatric solid tumors. The results of a detailed analysis of cell signaling in the neuroblastoma cell lines revealed that TKIs inhibited the phosphorylation of the corresponding receptor tyrosine kinases, and thiosemicarbazones downregulated the expression of epidermal growth factor receptor, platelet-derived growth factor receptor, and insulin-like growth factor-1 receptor, leading to a strong induction of apoptosis. Marked upregulation of the metastasis suppressor N-myc downstream regulated gene-1 (NDRG1), which is known to be activated and upregulated by thiosemicarbazones in adult cancers, was also detected in thiosemicarbazone-treated neuroblastoma cells. Importantly, these effects were more pronounced in the cells treated with drug combinations, especially with the combinations of lapatinib with thiosemicarbazones. Therefore, these results provide a rationale for novel strategies combining iron-chelating agents with TKIs in therapy of pediatric solid tumors.

• EGFR
• EGFR/HER2 heterodimers
• HER2
• absolute quantification
• breast cancer
• cancer cell heterogeneity
• correlative light- and liquid-phase electron microscopy
• gastric cancer
• single molecule detection

• Breast Neoplasms/metabolism
• Breast Neoplasms/ultrastructure
• Cell Line, Tumor
• Cell Membrane/metabolism
• Cell Surface Extensions/metabolism
• ErbB Receptors/metabolism
• Female
• Humans
• Microscopy, Electron
• Models, Biological
• Protein Multimerization
• Quantum Dots
• Receptor, ErbB-2/metabolism

• Drug resistance
• EGFR signaling
• Epidermal growth factor receptor (EGFR)
• Geometric properties
• Molecular dynamics (MD) simulations
• Signaling crosstalk

• Drug Resistance, Neoplasm/genetics
• ErbB Receptors/chemistry
• ErbB Receptors/genetics
• Genotype
• Humans
• Lung Neoplasms/drug therapy
• Lung Neoplasms/genetics
• Molecular Dynamics Simulation
• Mutant Proteins/chemistry
• Mutation/genetics
• Protein Kinase Inhibitors/pharmacology
• Protein Kinase Inhibitors/therapeutic use
• Proto-Oncogene Proteins c-met/metabolism
• Receptor, ErbB-2/metabolism
• Receptor, IGF Type 1/metabolism
• Signal Transduction/drug effects
• Signal Transduction/genetics

• Glyphosate-based herbicide
• ductal morphogenesis
• growth factors
• male
• rat mammary gland

• Actins/metabolism
• Animals
• Endocrine Disruptors/toxicity
• Female
• Glycine/analogs & derivatives
• Glycine/toxicity
• Herbicides/toxicity
• Intercellular Signaling Peptides and Proteins/biosynthesis
• MAP Kinase Signaling System/drug effects
• Male
• Mammary Glands, Animal/drug effects
• Mammary Glands, Animal/growth & development
• Pregnancy
• Prenatal Exposure Delayed Effects/pathology
• Rats
• Rats, Wistar
• Receptors, Estrogen/drug effects
• Receptors, Estrogen/genetics
• Receptors, Growth Factor/biosynthesis
• Receptors, Steroid/biosynthesis
• Glyphosate

• Cancer
• Pan-HER
• Target therapy

• Bcr-Abl
• Dependence receptors
• Epidermal growth factor receptor
• Receptor tyrosine kinases

• IGF system
• IGF-1R
• Insulin receptor
• Ovarian cancer
• System rewiring
• Targeted therapy

• Apoptosis
• DNA damage
• EGFR
• Heterodimerisation
• IGF1R
• Radiochemotherapy

Each member of the epidermal growth factor receptor (EGFR) family plays a key role in normal development, homeostasis, and a variety of pathophysiological conditions, most notably in cancer. According to the prevailing dogma, these four receptor tyrosine kinases (RTKs; EGFR, ERBB2, ERBB3, and ERBB4) function exclusively through the formation of homodimers and heterodimers within the EGFR family. These combinatorial receptor interactions are known to generate increased interactome diversity and therefore influence signaling output, subcellular localization and function of the heterodimer. This molecular plasticity is also thought to play a role in the development of resistance toward targeted cancer therapies aimed at these known oncogenes. Interestingly, many studies now challenge this dogma and suggest that the potential for EGFR family receptors to interact with more distantly related RTKs is much greater than currently appreciated. Here we discuss how the promiscuity of these oncogenic receptors may lead to the formation of many unexpected receptor pairings and the significant implications for the efficiency of many targeted cancer therapies.

• EGFR
• ERBB2
• ERBB3
• ERBB4
• cancer
• heterodimerisation
• receptor tyrosine kinase
• therapeutic resistance

EGFR mutation-induced drug resistance has become a major threat to the treatment of non-small-cell lung carcinoma. Essentially, the resistance mechanism involves modifications of the intracellular signaling pathways. In our work, we separately investigated the EGFR and ErbB-3 heterodimerization, regarded as the origin of intracellular signaling pathways. On one hand, we combined the molecular interaction in EGFR heterodimerization with that between the EGFR tyrosine kinase and its inhibitor. For 168 clinical subjects, we characterized their corresponding EGFR mutations using molecular interactions, with three potential dimerization partners (ErbB-2, IGF-1R and c-Met) of EGFR and two of its small molecule inhibitors (gefitinib and erlotinib). Based on molecular dynamics simulations and structural analysis, we modeled these mutant-partner or mutant-inhibitor interactions using binding free energy and its components. As a consequence, the mutant-partner interactions are amplified for mutants L858R and L858R_T790M, compared to the wild type EGFR. Mutant delL747_P753insS represents the largest difference between the mutant-IGF-1R interaction and the mutant-inhibitor interaction, which explains the shorter progression-free survival of an inhibitor to this mutant type. Besides, feature sets including different energy components were constructed, and efficient regression trees were applied to map these features to the progression-free survival of an inhibitor. On the other hand, we comparably examined the interactions between ErbB-3 and its partners (EGFR mutants, IGF-1R, ErbB-2 and c-Met). Compared to others, c-Met shows a remarkably-strong binding with ErbB-3, implying its significant role in regulating ErbB-3 signaling. Moreover, EGFR mutants corresponding to poor clinical outcomes, such as L858R_T790M, possess lower binding affinities with ErbB-3 than c-Met does. This may promote the communication between ErbB-3 and c-Met in these cancer cells. The analysis verified the important contribution of IGF-1R or c-Met in the drug resistance mechanism developed in lung cancer treatments, which may bring many benefits to specialized therapy design and innovative drug discovery.

• Carcinoma, Non-Small-Cell Lung/drug therapy
• Carcinoma, Non-Small-Cell Lung/genetics
• Disease-Free Survival
• Drug Resistance, Neoplasm/genetics
• ErbB Receptors/chemistry
• ErbB Receptors/genetics
• Erlotinib Hydrochloride/pharmacology
• Erlotinib Hydrochloride/therapeutic use
• Gefitinib
• Humans
• Lung Neoplasms/drug therapy
• Lung Neoplasms/genetics
• Molecular Dynamics Simulation
• Mutant Proteins/chemistry
• Mutation/genetics
• Protein Binding/drug effects
• Protein Kinase Inhibitors/pharmacology
• Protein Kinase Inhibitors/therapeutic use
• Protein Multimerization/drug effects
• Quinazolines/pharmacology
• Quinazolines/therapeutic use
• Receptor, ErbB-3/metabolism
• Regression Analysis
• Signal Transduction/drug effects
• Signal Transduction/genetics
• Structural Homology, Protein
• Thermodynamics

• GPR30/GPER
• cancer cells
• cancer-associated fibroblasts
• estrogen receptor
• insulin/IGF system
• signal transduction

• Antineoplastic Agents/toxicity
• Carcinoma, Squamous Cell/metabolism
• Cell Line, Tumor
• Dose-Response Relationship, Drug
• ErbB Receptors/antagonists & inhibitors
• ErbB Receptors/metabolism
• Esophageal Neoplasms/metabolism
• Humans
• Microtubules/metabolism
• Phosphorylation/drug effects
• Podophyllotoxin/analogs & derivatives
• Podophyllotoxin/toxicity
• Protein Kinase Inhibitors/pharmacology
• Receptor, IGF Type 1/antagonists & inhibitors
• Receptor, IGF Type 1/metabolism
• Signal Transduction/drug effects
• Tubulin Modulators/pharmacology

Aberrant expression and activation of the IGF-IR have been reported in a variety of human cancers and have been associated with resistance to HER targeted therapy. In this study, we investigated the effect of simultaneous targeting of IGF-IR and HER (erbB) family, with NVP-AEW541 and afatinib, on proliferation of pancreatic cancer cells.

The sensitivity of a panel of human pancreatic cancer cell lines to treatment with NVP-AEW541 used alone or in combination with afatinib, anti-EGFR antibody ICR62, and cytotoxic agents was determined using the Sulforhodamine B colorimetric assay. Growth factor receptor expression, cell-cycle distribution and cell signalling were determined using flow cytometry and western blot analysis.

All pancreatic cancer cell lines were found to be IGF-IR positive and NVP-AEW541 treatment inhibited the growth of the pancreatic cancer cell lines with IC50 values ranging from 342 nM (FA6) to 2.73 μM (PT45). Interestingly, of the various combinations examined, treatment with a combination of NVP-AEW541 and afatinib was superior in inducing synergistic growth inhibition of the majority of pancreatic cancer cells.

Our results indicate that co-targeting of the erbB (HER) family and IGF-IR, with a combination of afatinib and NVP-AEW541, is superior to treatment with a single agent and encourages further investigation in vivo on their therapeutic potential in IGF-IR and HER positive pancreatic cancers.

The clinical success of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) as therapeutic agents has prompted great interest in their further development and clinical testing for a wide variety of malignancies. However, most studies have focused on the efficacy of TKI, and few studies have been done on the criteria for their discontinuation. The current standard for drug discontinuation is “until progression”, based on change in tumor size. However, tumor size is not related to the gene expression which determines the efficacy of TKI in the final analysis, and it is also difficult to make a thorough and correct prediction based on tumor size when the TKI is discontinued. Nevertheless, clinical evaluation of the criteria for TKI discontinuation is still in its early days. Some promising findings have started to emerge. With the improving knowledge of EGFR and its inhibitors, it is expected that the criteria for discontinuation of EGFR inhibitor therapy will become clearer.

• acquired drug-resistance
• drug discontinuation
• epidermal growth factor receptor

Mammary gland development and breast cancer growth require multiple factors both of endocrine and paracrine origin. We analyzed the roles of Epidermal Growth Factor Receptor (EGFR) and Hepatocyte Growth Factor Receptor (Met) in mammary epithelial cells and mammary tumor cells derived from a mutated-ErbB2 transgenic mice. By using highly specific tyrosine kinase inhibitors we found that MCF-10A and NMuMG mammary epithelial cell lines are totally dependent on EGFR activation for their growth and survival. Proliferation and 3D-morphogenesis assays showed that HGF had no role in maintaining mammary cell viability, but was the only cytokine able to rescue EGFR-inhibited mammary cells. Insulin-Like Growth Factor-I (IGF-I), basic-Fibroblast Growth Factor (b-FGF) and Neuregulin, which are well known mammary morphogenic factors, did not rescue proliferation or morphogenesis in these cell lines, following EGFR inhibition. Similarly, ErbB2-driven tumor cells are EGFR-dependent and also display HGF-mediated rescue. Western-blot analysis of the signaling pathways involved in rescue after EGFR inhibition indicated that concomitant ERK1/2 and AKT activation was exclusively driven by Met, but not by IGF-I or b-FGF. These results describe a unique role for EGFR and Met in mammary epithelial cells by showing that similar pathways can be used by tumorigenic cells to sustain growth and resist to EGFR-directed anti-tumorigenic drugs.

• Animals
• Breast Neoplasms/enzymology
• Breast Neoplasms/pathology
• Cell Line, Tumor
• Cell Proliferation/drug effects
• Cell Survival/drug effects
• Enzyme Activation/drug effects
• Epidermal Growth Factor/pharmacology
• Epithelial Cells/drug effects
• Epithelial Cells/enzymology
• Epithelial Cells/pathology
• ErbB Receptors/metabolism
• Extracellular Signal-Regulated MAP Kinases/metabolism
• Female
• Hepatocyte Growth Factor/pharmacology
• Humans
• Mammary Glands, Animal/drug effects
• Mammary Glands, Animal/enzymology
• Mammary Glands, Animal/growth & development
• Mammary Glands, Animal/pathology
• Mammary Glands, Human/drug effects
• Mammary Glands, Human/enzymology
• Mammary Glands, Human/growth & development
• Mammary Glands, Human/pathology
• Mice
• Mice, Transgenic
• Morphogenesis/drug effects
• Phosphorylation/drug effects
• Proto-Oncogene Proteins c-akt/metabolism
• Proto-Oncogene Proteins c-met/metabolism
• Receptor, ErbB-2/metabolism
• Signal Transduction/drug effects

• Animals
• Cell Differentiation
• Cell Proliferation
• Cell Survival
• Humans
• Insulin/metabolism
• Insulin-Like Growth Factor Binding Protein 3/metabolism
• Intracellular Signaling Peptides and Proteins/metabolism
• Receptor Cross-Talk
• Receptor Protein-Tyrosine Kinases/metabolism
• Signal Transduction
• Somatomedins/metabolism

Gonadotrophin releasing hormone (GnRH) analogs lower estrogen levels in pre-menopausal breast cancer patients. GnRH receptor (GnRH-R) activation also directly inhibits the growth of certain cells. The applicability of GnRH anti-proliferation to breast cancer was therefore analyzed.

GnRH-R expression in 298 primary breast cancer samples was measured by quantitative immunofluorescence. Levels of functional GnRH-R in breast-derived cell lines were assessed using ¹²⁵I-ligand binding and stimulation of ³H-inositol phosphate production. Elevated levels of GnRH-R were stably expressed in cells by transfection. Effects of receptor activation on in vitro cell growth were investigated in comparison with IGF-I and EGF receptor inhibition, and correlated with intracellular signaling using western blotting.

GnRH-R immunoscoring was highest in hormone receptor (triple) negative and grade 3 breast tumors. However prior to transfection, functional endogenous GnRH-R were undetectable in four commonly studied breast cancer cell lines (MCF-7, ZR-75-1, T47D and MDA-MB-231). After transfection with GnRH-R, high levels of cell surface GnRH-R were detected in SVCT and MDA-MB-231 clones while low-moderate levels of GnRH-R occurred in MCF-7 clones and ZR-75-1 clones. MCF-7 sub-clones with high levels of GnRH-R were isolated following hygromycin phosphotransferase transfection. High level cell surface GnRH-R enabled induction of high levels of ³H-inositol phosphate and modest growth-inhibition in SVCT cells. In contrast, growth of MCF-7, ZR-75-1 or MDA-MB-231 clones was unaffected by GnRH-R activation. Cell growth was inhibited by IGF-I or EGF receptor inhibitors. IGF-I receptor inhibitor lowered levels of p-ERK1/2 in MCF-7 clones. Washout of IGF-I receptor inhibitor resulted in transient hyper-elevation of p-ERK1/2, but co-addition of GnRH-R agonist did not alter the dynamics of ERK1/2 re-phosphorylation.

Breast cancers exhibit a range of GnRH-R immunostaining, with higher levels of expression found in triple-negative and grade 3 cancers. However, functional cell surface receptors are rare in cultured cells. Intense GnRH-R signaling in transfected breast cancer cells did not markedly inhibit growth, in contrast to transfected HEK 293 cells indicating the importance of intracellular context. GnRH-R signaling could not counteract IGF-I receptor-tyrosine kinase addiction in MCF-7 cells. These results suggest that combinatorial strategies with growth factor inhibitors will be needed to enhance GnRH anti-proliferative effects in breast cancer

The transcription factor, CCAAT enhancer binding protein-β (C/EBPβ), is expressed as several distinct protein isoforms (LAP1, LAP2 and LIP) that have opposing actions in cellular proliferation and differentiation. Increases in the ratio of LIP/LAP are associated with aggressive, metastatic breast cancer; however, little is known regarding the molecular mechanisms that regulate LIP expression or the biological actions of an increase in the LIP/LAP ratio. Metastasis is highly dependent upon the suppression of anoikis and the role of C/EBPβ and LIP in this anchorage-independent, survival process is currently not known in mammary epithelial cells. IGF-1R signaling is important for the survival of breast cancer cells and crosstalk between IGF-1R and EGFR signaling pathways have been implicated in the development of more aggressive disease. We therefore evaluated in mammary epithelial cells whether IGF-1R signaling regulates the LIP/LAP ratio, analyzed the potential interplay between EGFR and IGF-1R signaling and addressed the biological significance of increased LIP expression in cellular survival and suppression of anoikis.

Our data provide the first evidence that IGF-1R signaling regulates LIP expression in an EGFR independent manner to increase the LIP/LAP ratio in mammary epithelial cells. Although crosstalk between IGF-1R signaling and EGFR signaling is detectable in MCF10A cells, this crosstalk is not required for the IGF-1 mediated regulation of LIP expression. Rather, the critical regulator of IGF-1 induced LIP expression appears to be EGFR-independent, Akt activity. Our data also demonstrate that increases in LIP expression promote cell survival via suppression of anoikis. Likewise, knockdown of total C/EBPβ leads to increased cell death and suggest that C/EBPβ expression is important for survival and resistance to anoikis. IGF-1 treatment can partially rescue vector control cells from anoikis; however, cells with reduced C/EBPβ expression do not survive anoikis.

Taken together, our data demonstrate that IGF-1R signaling regulates LIP expression in an EGFR independent manner to increase the LIP/LAP ratio in mammary epithelial cells. C/EBPβ expression and elevations in LIP play an important role in regulating cellular survival via suppression of anoikis, in an IGF-1R mediated context or in a manner independent of IGF-1R signaling.

An organotypic model of endometrial carcinogenesis and chemoprevention was developed in which normal endometrial organotypic cultures exposed to the carcinogen, DMBA (7,12-dimethylbenz[a]anthracene), developed a cancerous phenotype in the absence, but not presence of subsequent treatment with a flexible heteroarotinoid (Flex-Het), called SHetA2. A discriminant function based on karyometric features of cellular nuclei and an agar clonogenic assay confirmed these histologic changes. Interpretation of microarray data using an internal standard approach identified major pathways associated with carcinogenesis and chemoprevention governed by c-myc, p53, TNFα and Jun genes. Cluster analysis of functional associations of hypervariable genes demonstrated that carcinogenesis is accompanied by a stimulating association between a module of genes that includes tumor necrosis factor α (TNFα), c-myc, and epidermal growth factor-receptor (EGF-R) and a module that includes insulin-like growth factor I-receptor (IGF-IR), p53, and Jun genes. Two secreted proteins involved in these systems, tenascin C and inhibin A, were validated at the protein level. Tenascin C is an EGF-R ligand, and therefore may contribute to the increased EGF-R involvement in carcinogenesis. The known roles of the identified molecular systems in DMBA and endometrial carcinogenesis and chemoprevention supports the validity of this model and the potential clinical utility of SHetA2 in chemoprevention.

• carcinogenesis
• chemoprevention
• endometrial cancer
• heteroarotinoid
• karyometric analysis
• microarrays

• Antineoplastic Agents, Hormonal/pharmacology
• Apoptosis
• Breast Neoplasms/drug therapy
• Breast Neoplasms/metabolism
• Cell Line, Tumor
• Drug Resistance, Neoplasm/drug effects
• ErbB Receptors/metabolism
• Estradiol/analogs & derivatives
• Estradiol/pharmacology
• Estrogen Receptor alpha/genetics
• Estrogen Receptor alpha/metabolism
• Estrogens/metabolism
• Female
• Fulvestrant
• Gene Expression Regulation, Neoplastic/drug effects
• Humans
• Mitogen-Activated Protein Kinases/metabolism
• Receptor, IGF Type 1/metabolism
• Signal Transduction/drug effects

• R01 CA065622 NCI NIH HHS
• R01 CA065622-16 NCI NIH HHS

Evaluating mitogenic signaling specifically through the human insulin receptor (IR) is relevant for the preclinical safety assessment of developmental insulin analogs. It is known that overexpression of IR sensitizes cells to the mitogenic effects of insulin, but it is essentially unknown how mitogenic responses can be optimized to allow practical use of such recombinant cell lines for preclinical safety testing. We constitutively overexpressed the short isoform of the human insulin receptor (hIR-A, exon 11-negative) in L6 rat skeletal myoblasts. Because the mitogenic effect of growth factors such as insulin is expected to act in G0/G1, promoting S-phase entry, we developed a combined topoinhibition + serum deprivation strategy to explore the effect of G0/G1 synchronization as an independent parameter in the context of serum deprivation, the latter being routinely used to reduce background in mitogenicity assays. G0/G1 synchronization significantly improved the mitogenic responses of L6-hIR cells to insulin, measured by ³H-thymidine incorporation. Comparison with the parental L6 cells using phospho-mitogen-activated protein kinase, phospho-AKT, as well as ³H-thymidine incorporation end points supported that the majority of the mitogenic effect of insulin in L6-hIR cells was mediated by the overexpressed hIR-A. Using the optimized L6-hIR assay, we found that the X-10 insulin analog was more mitogenic than native human insulin, supporting that X-10 exhibits increased mitogenic signaling through the hIR-A. In summary, this study provides the first demonstration that serum deprivation may not be sufficient, and G0/G1 synchronization may be required to obtain optimal responsiveness of hIR-overexpressing cell lines for preclinical safety testing.

• egfr
• epidermal growth factor receptor
• head and neck cancer
• signaling
• resistance pathways
• scchn

• Antibodies, Monoclonal/therapeutic use
• Apoptosis
• Carcinoma, Squamous Cell/drug therapy
• Carcinoma, Squamous Cell/metabolism
• Cell Cycle
• Drug Resistance, Neoplasm
• ErbB Receptors/antagonists & inhibitors
• ErbB Receptors/metabolism
• Head and Neck Neoplasms/drug therapy
• Head and Neck Neoplasms/metabolism
• Humans
• Protein Kinase Inhibitors/metabolism

• R01 CA113342 NCI NIH HHS
• R01 CA113342-02 NCI NIH HHS
• R01 CA063366-09 NCI NIH HHS
• R01 CA-113342 NCI NIH HHS
• P30 CA006927 NCI NIH HHS
• CA-06927 NCI NIH HHS
• R01 CA063366 NCI NIH HHS
• R01 CA-63366 NCI NIH HHS

• pten
• antiestrogen
• breast cancer
• igf-ir
• erbb3

• Animals
• Breast Neoplasms/metabolism
• ErbB Receptors/metabolism
• Humans
• Proto-Oncogene Proteins/classification
• Proto-Oncogene Proteins/metabolism
• Receptor, IGF Type 1/metabolism
• Signal Transduction

• Animals
• Bone Marrow Cells/drug effects
• Bone Marrow Cells/metabolism
• Cell Degranulation/drug effects
• Cell Survival/drug effects
• Cells, Cultured
• Hydrogen Peroxide/metabolism
• Inositol Polyphosphate 5-Phosphatases
• Insulin/pharmacology
• Insulin-Like Growth Factor I/pharmacology
• Male
• Mast Cells/drug effects
• Mast Cells/metabolism
• Mice
• Mice, Knockout
• Phosphatidylinositol 3-Kinases/drug effects
• Phosphatidylinositol 3-Kinases/metabolism
• Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases
• Phosphoric Monoester Hydrolases/drug effects
• Phosphoric Monoester Hydrolases/metabolism
• Phosphorylation
• Proto-Oncogene Proteins c-akt/drug effects
• Proto-Oncogene Proteins c-akt/metabolism
• Signal Transduction/drug effects
• Signal Transduction/physiology
• p38 Mitogen-Activated Protein Kinases/drug effects
• p38 Mitogen-Activated Protein Kinases/metabolism

• Blotting, Western
• Breast Neoplasms/genetics
• Breast Neoplasms/metabolism
• Breast Neoplasms/pathology
• Cell Line, Tumor
• Cell Proliferation
• Epidermal Growth Factor/metabolism
• ErbB Receptors/genetics
• ErbB Receptors/metabolism
• Flow Cytometry
• Histone Acetyltransferases/antagonists & inhibitors
• Histone Acetyltransferases/genetics
• Histone Acetyltransferases/metabolism
• Humans
• Immunoprecipitation
• Nuclear Receptor Coactivator 3
• Phosphorylation
• RNA, Small Interfering/pharmacology
• Receptor, ErbB-3/metabolism
• Receptor, Platelet-Derived Growth Factor beta/metabolism
• Signal Transduction
• Trans-Activators/antagonists & inhibitors
• Trans-Activators/genetics
• Trans-Activators/metabolism
• Tyrosine/metabolism

• CA11677 NCI NIH HHS
• R01 CA113477 NCI NIH HHS
• CA108441 NCI NIH HHS
• R21 CA108441 NCI NIH HHS
• T32 CA009686 NCI NIH HHS

• Breast Neoplasms/physiopathology
• ErbB Receptors/physiology
• Female
• Humans
• Intercellular Signaling Peptides and Proteins/physiology
• Receptors, Estrogen/physiology
• Signal Transduction/physiology