GPER is involved in the regulation of the estrogen-metabolizing CYP1B1 enzyme in breast cancer
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Francesca Cirillo1,*, Michele Pellegrino1,*, Rocco Malivindi1, Vittoria Rago1, Silvia Avino1, Luigina Muto1, Vincenza Dolce1, Adele Vivacqua1, Damiano Cosimo Rigiracciolo1, Paola De Marco1, Anna Sebastiani1, Sergio Abonante2, Miki Nakajima3, Rosamaria Lappano1 and Marcello Maggiolini1
1Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy
2Regional Hospital Cosenza, Cosenza, Italy
3Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa, Japan
*These authors have contributed equally to this work
Marcello Maggiolini, email: [email protected], [email protected]
Rosamaria Lappano, email: [email protected], [email protected]
Keywords: breast cancer; cancer-associated fibroblasts; CYP1B1; estrogen; GPER
Received: September 07, 2017 Accepted: October 30, 2017 Published: November 20, 2017
The cytochrome P450 1B1 (CYP1B1) is a heme-thiolate monooxygenase involved in both estrogen biosynthesis and metabolism. For instance, CYP1B1 catalyzes the hydroxylation of 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 main players of the tumor microenvironment as cancer associated fibroblasts (CAFs) that were 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, our data suggest that estrogens in ER-negative cell contexts may engage the alternate GPER signaling toward CYP1B1 regulation. Estrogen-CYP1B1 landscape via GPER should be taken into account in setting novel pharmacological approaches targeting breast cancer development.
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