A positive feedback loop of ER-?36/EGFR promotes malignant growth of ER-negative breast cancer cells.

ABSTRACT: 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-?, ER-?36, and found that ER-?36 mediated nongenomic estrogen signaling and is highly expressed in ER-negative breast cancer cells. In this study, we found that ER-?36 was highly expressed in 10/12 cases of triple-negative breast cancer. We investigated the role of mitogenic estrogen signaling mediated by ER-?36 in malignant growth of triple-negative breast cancer MDA-MB-231 and MDA-MB-436 cells that express high levels of ER-?36 and found that these cells strongly responded to mitogenic estrogen signaling both in vitro and in vivo. Knockdown of ER-?36 expression in these cells using the small hairpin RNA method diminished their responsiveness to estrogen. ER-?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-?36 transcription through an AP1 site in the ER-?36 promoter, and ER-?36 expression was able to stabilize EGFR protein. Our results, thus demonstrated that ER-?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-?36, retains responsiveness to mitogenic estrogen signaling.

SUBMITTER: Zhang XT 

PROVIDER: S-EPMC3020987 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature