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-α, ER-α36, and found that ER-α36 mediated non-genomic 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 these cells were strongly responded to mitogenic estrogen signaling both in vitro and in vivo. Knock-down of ER-α36 expression in these cells using the shRNA method diminished their responsiveness to estrogen. ER-α36 physically interacted with the EGFR/Src/Shc complex and mediated estrogen-induced phosphorylation of 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 non-genomic 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 express ER-α36 retain responsiveness to mitogenic estrogen signaling.