title: Involvement of ER-α36, Src, EGFR and STAT5 in the biphasic estrogen             signaling of ER-negative breast cancer cells.
abstract: It is well established that estrogen is a potent mitogen in cells expressing estrogen receptors (ER). However, a large body of evidence has demonstrated that the effects of mitogenic estrogen signaling exhibit a non-monotonic or biphasic, dose-response curve; estrogen at low concentrations, elicits a mitogenic signaling pathway to stimulate cell proliferation, while at high concentrations, estrogen inhibits cell growth. The molecular mechanism underlying this paradoxical effect of estrogen on cell proliferation remains largely unknown. Recently, we reported that ER-α36, a variant of ER-α, mediates mitogenic estrogen signaling in ER-negative breast cancer cells. Here, we investigated the molecular mechanisms underlying the biphasic estrogen signaling in MDA-MB-231 and MDA-MB-436 ER-negative breast cancer cells. We found that 17β-estradiol (E2β) at l nM induced the phosphorylation of Src-Y416, an event that activates Src, while at 5 µM failed to induce Src-Y416 phosphorylation but induced Src-Y527 phosphorylation an event that inactivates Src. E2β at 1 nM, but not at 5 µM, also induced phosphorylation of MAPK/ERK and activated Cyclin D1 promoter activity through the Src/EGFR/STAT5 pathway. Knockdown of ER‑α36 abrogated the biphasic estrogen signaling in these cells. Our results thus indicate that in ER-negative breast cancer cells Src functions as a switch in ER‑α36-mediated biphasic estrogen signaling through the EGFR/STAT5 pathway.
authors.affiliation: Department of Medical Microbiology and Immunology, Creighton University Medical School, Omaha, NE 68178, USA.
authors.forename: Xin-Tian
authors.initials: XT
authors.lastname: Zhang
authors.forename: Ling
authors.initials: L
authors.lastname: Ding
authors.forename: Lian-Guo
authors.initials: LG
authors.lastname: Kang
authors.forename: Zhao-Yi
authors.initials: ZY
authors.lastname: Wang
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000096:biosynthesis / Q000235:genetics; D066246:ErbB Receptors / Q000378:metabolism*; D004958:Estradiol / Q000378:metabolism / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: C530104:CCND1 protein, human; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D050799:STAT5 Transcription Factor; D019938:Cyclin D1; D004958:Estradiol; C512478:EGFR protein, human; D066246:ErbB Receptors; D019061:src-Family Kinases; D048049:Extracellular Signal-Regulated MAP Kinases