G Protein-Coupled Receptor 30 Expression Is Up-Regulated by EGF and TGFα in Estrogen Receptor α-Positive Cancer Cells

Abstract

In the present study, we evaluated the regulation of G protein-coupled receptor (GPR)30 expression in estrogen receptor (ER)-positive endometrial, ovarian, and estrogen-sensitive, as well as tamoxifen-resistant breast cancer cells. We demonstrate that epidermal growth factor (EGF) and TGF alpha transactivate the GPR30 promoter and accordingly up-regulate GPR30 mRNA and protein levels only in endometrial and tamoxifen-resistant breast cancer cells. These effects exerted by EGF and TGF alpha were dependent on EGF receptor (EGFR) expression and activation and involved phosphorylation of the Tyr(1045) and Tyr(1173) EGFR sites. Using gene-silencing experiments and specific pharmacological inhibitors, we have ascertained that EGF and TGF alpha induce GPR30 expression through the EGFR/ERK transduction pathway, and the recruitment of c-fos to the activator protein-1 site located within GPR30 promoter sequence. Interestingly, we show that functional cross talk of GPR30 with both activated EGFR and ER alpha relies on a physical interaction among these receptors, further extending the potential of estrogen to trigger a complex stimulatory signaling network in hormone-sensitive tumors. Given that EGFR/HER2 overexpression is associated with tamoxifen resistance, our data may suggest that ligand-activated EGFR could contribute to the failure of tamoxifen therapy also by up-regulating GPR30, which in turn could facilitates the action of estrogen. In addition, important for resistance is the ability of tamoxifen to bind to and activate GPR30, the expression of which is up-regulated by EGFR activation. Our results emphasize the need for new endocrine agents able to block widespread actions of estrogen without exerting any stimulatory activity on transduction pathways shared by the steroid and growth factor-signaling networks.

GPER1 is regulated by insulin in cancer cells and cancer-associated fibroblasts

“…involved in tumor aggressiveness such as hypoxia, in the proliferation and migration of breast cancer cells and CAFs (Albanito et al 2008, Vivacqua et al 2009, Recchia et al 2011. Likewise, estrogens have been shown to stimulate growth effects in tamoxifen-resistant breast cancer cells through both an increased expression of GPER1 and the GPER1-mediated transactivation of EGFR (Ignatov et al 2011).…”

“…As regards the regulation of GPER1, our previous studies have shown that some important growth-factormediated transduction pathways such as EGFR (Albanito et al 2008, Vivacqua et al 2009) and IGF1 (Bartella et al 2012 are involved in the expression and function of GPER1 in cancer cells. Interestingly, high levels of expression of GPER1 in breast, endometrial, and ovarian tumors have been associated with a higher risk of developing metastatic disease and poor survival (Prossnitz & Barton 2011).…”

GPCRs and cancer

“…Moreover, it has been shown that the activation of the Gα s protein by GPER is responsible for the estrogen, phyto-and xenoestrogens stimulation of adenylate cyclase and the ensuing increase in cAMP in breast cancer cells [140,141] . The signaling events upon GPER activation by both estrogens and notably ER antagonists can lead to gene transcription as well as to the growth and migration in diverse hormone-sensitive tumors like breast, endometrial and ovarian cancer [142][143][144][145][146][147][148][149] . Notably, GPER was also involved in the stimulatory effects elicited by estrogens and ER antagonists in cancer-associated fibroblasts [147,150] .…”

Regulation of HRG-β1-induced proliferation, migration and invasion of MCF-7 cells by upregulation of GPR30 expression

“…In 2004 and 2005, two studies reported that 17-β-estradiol (E2) binds to and signals through GPR30 with high affinity and in vitro potency, respectively (5,6). GPR30 has been speculated to have a potentially important role in cancer progression, including breast, endometrial, prostate, ovarian and thyroid cancers (7)(8)(9)(10)(11)(12). A previous study, using a breast cancer patient specimen and cell model, showed that GPR30 signaling is involved in the development of endocrine therapy resistance (13,14).…”