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Zhang, XT, Kang, LG, Ding, L, Vranic, S, Gatalica, Z and Wang, ZY (2011) A positive feedback loop of ER-α36/EGFR promotes malignant growth of ER-negative breast cancer cells. Oncogene 30:770-80

It is prevailingly thought that estrogen signaling is not involved in development of estrogen receptor (ER)-negative breast cancer. However, there is evidence indicating that ovariectomy prevents the development of both ER-positive and -negative breast cancer, suggesting that estrogen signaling is involved in the development of ER-negative breast cancer. Previously, our laboratory cloned a variant of ER-α, ER-α36, and found that ER-α36 mediated nongenomic estrogen signaling and is highly expressed in ER-negative breast cancer cells. In this study, we found that ER-α36 was highly expressed in 10/12 cases of triple-negative breast cancer. We investigated the role of mitogenic estrogen signaling mediated by ER-α36 in malignant growth of triple-negative breast cancer MDA-MB-231 and MDA-MB-436 cells that express high levels of ER-α36 and found that these cells strongly responded to mitogenic estrogen signaling both in vitro and in vivo. Knockdown of ER-α36 expression in these cells using the small hairpin RNA method diminished their responsiveness to estrogen. ER-α36 physically interacted with the EGFR/Src/Shc complex and mediated estrogen-induced phosphorylation of epidermal growth factor receptor (EGFR) and Src. EGFR signaling activated ER-α36 transcription through an AP1 site in the ER-α36 promoter, and ER-α36 expression was able to stabilize EGFR protein. Our results, thus demonstrated that ER-α36 mediates nongenomic estrogen signaling through the EGFR/Src/ERK signaling pathway in ER-negative breast cancer cells and suggested that a subset of ER-negative breast tumors that expresses ER-α36, retains responsiveness to mitogenic estrogen signaling.

PubMed PMC3020987 Online version:10.1038/onc.2010.458

Animals; Antineoplastic Agents, Hormonal/pharmacology; Breast Neoplasms/metabolism; Breast Neoplasms/pathology; Carcinoma/drug therapy; Carcinoma/metabolism; Cell Line, Tumor; Cell Proliferation/drug effects; Chromones/pharmacology; Enzyme Inhibitors/pharmacology; Estrogen Receptor alpha/metabolism; Estrogens/metabolism; Estrogens/pharmacology; Feedback, Physiological; Female; Humans; Mice; Mice, Nude; Morpholines/pharmacology; Ovariectomy; Pyrimidines/metabolism; RNA, Small Interfering/genetics; Receptor, Epidermal Growth Factor/metabolism; Shc Signaling Adaptor Proteins/metabolism; src-Family Kinases/metabolism