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Estrogen Negatively Regulates Epidermal Growth Factor (EGF)-Mediated Signal Transducer and Activator of Transcription 5 Signaling in Human EGF Family Receptor-Overexpressing Breast Cancer Cells

Departments of Microbiology (J.L.B., E.D.P., S.J.P., C.M.S.), Internal Medicine-Endocrinology (M.A.G., E.D.P., C.M.S., M.A.S.), and Pharmacology (E.M.F.), and The Cancer Center of the University of Virginia (S.J.P., C.M.S., M.A.S.), Charlottesville, Virginia 22908

Address all correspondence and requests for reprints to: Margaret A. Shupnik, Department of Internal Medicine-Endocrinology, University of Virginia, Charlottesville, Virginia 22908. E-mail: mas3x{at}virginia.edu.

Breast cancer cell growth may be stimulated by 17ß-estradiol (E2) or growth factors like epidermal growth factor (EGF). However, tumors typically depend on only one of these pathways and may overexpress either estrogen receptor (ER) or EGF receptor (EGFR) and related family members. Tumors overexpressing EGFR are more aggressive than those expressing ER. Intracellular mediators of these growth-stimulatory pathways are not completely defined, but one potential common mediator of EGF and E2 signaling is the transcription factor signal transducer and activator of transcription 5 (STAT5). To investigate the role of STAT5 in potential crosstalk between E2 and EGF, MDA-MB231 and SKBr3 breast cancer cells, which are ER-negative and overexpress human EGF family receptors, were used. Introduction of ER and treatment with E2 decreased EGF-induced tyrosine phosphorylation of STAT5b, basal and EGF-induced STAT5-mediated transcription, and EGF-stimulated DNA synthesis in these cells. Suppressive effects of E2-ER were specific for STAT5, as EGF stimulation of MAPK was unaffected. Deletion/mutation analysis of ER demonstrated that the DNA-binding domain was insufficient, and that the ligand-binding domain was required for these responses. ER transcriptional activity was not necessary for suppression of STAT5 activity. Overexpression of c-Src did not prevent suppression of STAT5 activity by E2 and ER. However, ER did prevent basal increases in STAT5 activity with overexpressed c-Src. In the context of human EGF receptor family overexpression, E2-ER opposes EGF signaling by regulating STAT5 activity. STAT5 may be a crucial point of signaling for both E2 and growth factors in breast cancer cells, allowing targeted therapy for many types of breast tumors.

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα

Ligands:   17β-Estradiol

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