Cirillo Francesca, Pellegrino Michele, Malivindi Rocco, Rago Vittoria, Avino Silvia, Muto Luigina, Dolce Vincenza, Vivacqua Adele, Rigiracciolo Damiano Cosimo, De Marco Paola, Sebastiani Anna, Abonante Sergio, Nakajima Miki, Lappano Rosamaria, Maggiolini Marcello
Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy.
Regional Hospital Cosenza, Cosenza, Italy.
Oncotarget. 2017 Nov 20;8(63):106608-106624. doi: 10.18632/oncotarget.22541. eCollection 2017 Dec 5.
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 and . 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.
细胞色素P450 1B1（CYP1B1）是一种血红素硫醇盐单加氧酶，参与雌激素的生物合成和代谢。例如，CYP1B1催化E2的羟基化反应，生成可能作为强效致癌剂的4-羟基雌二醇。此外，CYP1B1在包括乳腺癌在内的不同肿瘤中过表达。在这种情况下，值得一提的是，在乳腺癌细胞中，雌激素通过雌激素受体（ER）α触发CYP1B1的表达。在本研究中，我们评估了G蛋白雌激素受体即GPER是否可能为雌激素受体阴性乳腺癌细胞、从乳腺癌患者获取的肿瘤微环境主要成分癌相关成纤维细胞（CAFs）、源自浸润性乳腺导管癌皮肤转移灶的CAFs以及乳腺肿瘤异种移植瘤中CYP1B1的表达和功能提供另一条途径。我们的结果表明，GPER与表皮生长因子受体/细胞外信号调节激酶/c-Fos转导途径一起，可通过CYP1B1启动子区域内的一个半雌激素反应元件（half-ERE）序列参与导致CYP1B1的调控。作为生物学对应物，我们发现GPER和CYP1B1均介导生长效应。总之，我们的数据表明，在雌激素受体阴性的细胞环境中，雌激素可能通过替代的GPER信号传导来调控CYP1B1。在制定针对乳腺癌发展的新型药理学方法时，应考虑通过GPER的雌激素-CYP1B1格局。
