Estrogenic GPR30 signalling induces proliferation and migration of breast cancer cells through CTGF

Abstract

The steroid hormone oestrogen can signal through several receptors and pathways. Although the transcriptional responses mediated by the nuclear oestrogen receptors (ER) have been extensively characterized, the changes in gene expression elicited by signalling through the membraneassociated ER GPR30 have not been studied. We show here for ER-negative human breast cancer cells that the activation of GPR30 signalling by oestrogen or by hydroxytamoxifen (OHT), an ER antagonist but GPR30 agonist, induces a transcription factor network, which resembles that induced by serum in fibroblasts. The most strongly induced gene, CTGF, appears to be a target of these transcription factors. We found that the secreted factor connective tissue growth factor (CTGF) not only contributes to promote proliferation but also mediates the GPR30-induced stimulation of cell migration. These results provide a framework for understanding the physiological and pathological functions of GPR30. As the activation of GPR30 by OHT also induces CTGF in fibroblasts from breast tumour biopsies, these pathways may be involved in promoting aggressive behaviour of breast tumours in response to endogenous oestrogens or to OHT being used for endocrine therapy.

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

“…Noteworthily, GPER1 and one of its main target genes, CTGF, were required for cell migration induced by insulin. As CTGF has been mainly involved in cell motility (Chu et al 2008, Pandey et al 2009), the GPER1/CTGF signaling activated by insulin might contribute to the invasion abilities of cancer cells during cancer development and metastasis.…”

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] .…”

In Vivo Functions of GPR30/GPER-1, a Membrane Receptor for Estrogen: From Discovery to Functions In Vivo

“…The activated EGF receptor also induces ERk activation [22,23]. in a recent paper, it was reported that the activation of ERk through GPR30 after E2 stimulation results in the secretion of a growth factor, cTGF, into the extracellular space, and that this secretion is involved in the proliferation of breast cancer cells [24]. These signal pathways in response to E2 appear to lead to the proliferation of breast cancer cells.…”