1. Estrogen Receptor-Alpha 36 Mediates Mitogenic Antiestrogen Signaling in ER-Negative Breast Cancer Cells
- Author
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Ling Ding, Xin-Tian Zhang, Zhao-Yi Wang, and Lianguo Kang
- Subjects
MAPK/ERK pathway ,lcsh:Medicine ,0302 clinical medicine ,Estrogen Receptor Modulators ,Molecular Cell Biology ,polycyclic compounds ,Membrane Receptor Signaling ,Phosphorylation ,lcsh:Science ,skin and connective tissue diseases ,Fulvestrant ,0303 health sciences ,Multidisciplinary ,Estradiol ,Obstetrics and Gynecology ,3. Good health ,Oncology ,030220 oncology & carcinogenesis ,Medicine ,Female ,Signal transduction ,hormones, hormone substitutes, and hormone antagonists ,Proto-oncogene tyrosine-protein kinase Src ,medicine.drug ,Research Article ,Signal Transduction ,medicine.drug_class ,Morpholines ,Blotting, Western ,Immunoblotting ,Breast Neoplasms ,Biology ,03 medical and health sciences ,Cell Line, Tumor ,medicine ,Humans ,Immunoprecipitation ,030304 developmental biology ,Cell Proliferation ,lcsh:R ,Estrogen Receptor alpha ,Computational Biology ,Cancers and Neoplasms ,Molecular Development ,Antiestrogen ,Estrogen ,Chromones ,Cancer research ,lcsh:Q ,Hydroxytestosterones ,Estrogen receptor alpha ,Tamoxifen ,Developmental Biology - Abstract
It is prevailingly thought that the antiestrogens tamoxifen and ICI 182, 780 are competitive antagonists of the estrogen-binding site of the estrogen receptor-alpha (ER-α). However, a plethora of evidence demonstrated both antiestrogens exhibit agonist activities in different systems such as activation of the membrane-initiated signaling pathways. The mechanisms by which antiestrogens mediate estrogen-like activities have not been fully established. Previously, a variant of ER-α, EP-α36, has been cloned and showed to mediate membrane-initiated estrogen and antiestrogen signaling in cells only expressing ER-α36. Here, we investigated the molecular mechanisms underlying the antiestrogen signaling in ER-negative breast cancer MDA-MB-231 and MDA-MB-436 cells that express high levels of endogenous ER-α36. We found that the effects of both 4-hydoxytamoxifen (4-OHT) and ICI 182, 780 (ICI) exhibited a non-monotonic, or biphasic dose response curve; antiestrogens at low concentrations, elicited a mitogenic signaling pathway to stimulate cell proliferation while at high concentrations, antiestrogens inhibited cell growth. Antiestrogens at l nM induced the phosphorylation of the Src-Y416 residue, an event to activate Src, while at 5 µM induced Src-Y527 phosphorylation that inactivates Src. Antiestrogens at 1 nM also induced phosphorylation of the MAPK/ERK and activated the Cyclin D1 promoter activity through the Src/EGFR/STAT5 pathways but not at 5 µM. Knock-down of ER-α36 abrogated the biphasic antiestrogen signaling in these cells. Our results thus indicated that ER-α36 mediates biphasic antiestrogen signaling in the ER-negative breast cancer cells and Src functions as a switch of antiestrogen signaling dependent on concentrations of antiestrogens through the EGFR/STAT5 pathway.
- Published
- 2012