Functional cooperation between GPER and AHR toward breast cancer progression

The cytochrome P450 1B1 (CYP1B1) is a heme-thiolate monooxygenase involved in both estrogen and environmental contaminants metabolism. For instance, CYP1B1 catalyzes the hydroxylation of 17-β estradiol (E2) leading to the production of 4-hydroxyestradiol that may act as a potent carcinogenic agent. In addition, CYP1B1 is overexpressed in different tumors including breast cancer. In this scenario, it is worth mentioning that CYP1B1 expression is triggered by estrogens through the estrogen receptor (ER)α in breast cancer cells. In the present study, we evaluated whether the G protein estrogen receptor namely GPER may provide an alternate route toward the expression and function of CYP1B1 in ER-negative breast cancer cells, in cancer-associated fibroblasts (CAFs) obtained from breast cancer patients, in CAFs derived from a cutaneous metastasis of an invasive mammary ductal carcinoma and in breast tumor xenografts. Our results show that GPER along with the EGFR/ERK/c-Fos transduction pathway can lead to CYP1B1 regulation through the involvement of a half-ERE sequence located within the CYP1B1 promoter region. As a biological counterpart, we found that both GPER and CYP1B1 mediate growth effects in vitro and in vivo. Altogether, these data suggest that estrogens in ER-negative cell contexts may engage the alternate GPER signaling toward CYP1B1 regulation. CYP1B1 is a well-known target gene of the aryl hydrocarbon receptor (AHR) that may be activated by the carcinogenic pollutant 3-methylcholanthrene (3MC). Hence, we aimed to provide novel insights into the molecular mechanisms by which 3MC and E2 may activate a cross talk between AHR and GPER transduction pathways leading to the stimulation of breast cancer cells and CAFs. In particular, our results demonstrate that 3MC and E2 trigger the EGFR/ERK/c-Fos signalling through both AHR and GPER toward the up-regulation of CYP1B1 and cyclin D1 as well as the stimulation of growth responses. Altogether, the present findings suggest that a functional interaction between AHR and GPER may occur toward breast cancer progression