A positive feedback loop of ER-α36/EGFR promotes malignant growth of ER-negative breast cancer cells

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-alpha, ER-alpha 36, and found that ER-alpha 36 mediated nongenomic estrogen signaling and is highly expressed in ER-negative breast cancer cells. In this study, we found that ER-alpha 36 was highly expressed in 10/12 cases of triple-negative breast cancer. We investigated the role of mitogenic estrogen signaling mediated by ER-alpha 36 in malignant growth of triple-negative breast cancer MDA-MB-231 and MDA-MB-436 cells that express high levels of ER-alpha 36 and found that these cells strongly responded to mitogenic estrogen signaling both in vitro and in vivo. Knockdown of ER-alpha 36 expression in these cells using the small hairpin RNA method diminished their responsiveness to estrogen. ER-alpha 36 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-alpha 36 transcription through an AP1 site in the ER-alpha 36 promoter, and ER-alpha 36 expression was able to stabilize EGFR protein. Our results, thus demonstrated that ER-alpha 36 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-alpha 36, retains responsiveness to mitogenic estrogen signaling. Oncogene (2011) 30, 770-780; doi:10.1038/onc.2010.458; published online 11 October 2010