Novel interactions between ERα-36 and STAT3 mediate breast cancer cell migration

Abstract

Background Breast cancer is the leading cause of cancer death in women worldwide which is closely related to metastasis. But the exact molecular mechanism of ERα-36 and STAT3 on metastasis is still not fully understood. Methods MCF-7 and MDA-MB-231 human breast cancer cell lines and MCF-10A were overexpressioned or knockdown ERα-36 and STAT3 and tested for migration, invasion and proliferation assays. Direct interaction of STAT3 and ERα-36 were analyzed by coimmunoprecipitation assays. The effect of STAT3 and ERα-36 on MMP2/9 expression was analyzed by qPCR and western blotting. STAT3 phospholyation and acetylation by ERα-36 and p300 were observed and quantified by coimmunoprecipitation assays and western blotting. Results Cross-talk between ERα-36 and STAT3 was demonstrated to mediate through a direct physical association between the two proteins. Furthermore, the interaction between ERα-36 and STAT3 was demonstrated to give rise to functional changes in their signaling events. Both MMP2 and MMP9 expression require the binding of the newly identified protein complex, ERα-36-STAT3, to its promoter, the second phase, which is more robust, depends on ERα-mediated recruitment of p300 onto the complex and the subsequent acetylation of STAT3. In addition, STAT3 is tyrosine-phosphorylated in a biphasic manner, and the late phase requires ERα-36-mediated p300-dependent acetylation. Furthermore, interference with acetylation of STAT3 by overexpression of acetylation null STAT3 mutant led to the loss of MMP2 and MMP9 expression. ChIP analysis and reporter gene assays revealed that ERα-36-STAT3 complex binding to the MMP2 and MMP9 promoter led to an enhanceosome formation and facilitated MMP2 and MMP9 expression. Conclusions Our studies demonstrate for the first time that the function of MMP2 and MMP9 in breast cancer cell migration, which is mediated by interactions between ERα-36 and STAT3.

G6PD upregulates Cyclin E1 and MMP9 to promote clear cell renal cell carcinoma progression

“…ROS promotes and interacts with numerous oncogenic signaling pathways, such as the STAT3, MAPK and NF-κB pathways, to favor the development of human cancers. Moreover, proliferation and metastasis related genes, such as cyclins and MMPs, which were transcriptional regulation targets of these oncogenic signaling transducers [37][38][39][40] and were found to be involved in this ROS-mediated mechanisms of action in ccRCC [12,21,41]. These implies that ROS and its relevant signaling pathways might be involved in the G6PD-mediated upregulation of Cyclin E1 and MMP9 in our study.…”

ERα36–GPER1 Collaboration Inhibits TLR4/NFκB-Induced Pro-Inflammatory Activity in Breast Cancer Cells

“…More such interactions of ERα36 with other transcription factors have been reported [ 14 ]. Although we did not find any effect of ERα36 on cellular migration, ERα36 has been found to regulate STAT3-mediated increased migration as well as MMP2 and MMP9 promoter activity in breast cancer cells treated with IL-6 [ 52 ]. These findings suggest the role of ERα36 in regulating tethered actions of other critical transcription factors, even in the absence of estrogen.…”

ELTD1 promotes invasion and metastasis by activating MMP2 in colorectal cancer

“…Through ChIP and luciferase promoter assays, Teng et al 31 found that HMGA1 can bind to the promoter region of MMP2 and promote the transcription of MMP2 in liver cancer cells. Xiang et al 32 found that the ERα-36-STAT3 complex could directly bind to the promoter regions of MMP2/9 and promote their expression in breast cancer cells. In another study, ChIP analyses indicated that MMP2 transcription was directly regulated by RARα 33 .…”