ESTROGENIC GPR30 SIGNALLING INDUCES PROLIFERATION AND MIGRATION OF BREAST CANCER CELLS THROUGH CTGF

The steroid hormone oestrogen can signal through severalreceptors and pathways. Although the transcriptional responsesmediated by the nuclear oestrogen receptors (ER)have been extensively characterized, the changes in geneexpression elicited by signalling through the membraneassociatedER GPR30 have not been studied.We show herefor ER-negative human breast cancer cells that the activationof GPR30 signalling by oestrogen or by hydroxytamoxifen(OHT), an ER antagonist but GPR30 agonist,induces a transcription factor network, which resemblesthat induced by serum in fibroblasts. The most stronglyinduced gene, CTGF, appears to be a target of thesetranscription factors. We found that the secreted factorconnective tissue growth factor (CTGF) not only contributesto promote proliferation but also mediates theGPR30-induced stimulation of cell migration. Theseresults provide a framework for understanding the physiologicaland pathological functions of GPR30. As theactivation of GPR30 by OHT also induces CTGF in fibroblastsfrom breast tumour biopsies, these pathways maybe involved in promoting aggressive behaviour of breasttumours in response to endogenous oestrogens or to OHT being used for endocrine therapy.