GPER, IGF-IR, and EGFR transduction signaling are involved in stimulatory effects of zinc in breast cancer cells and cancer-associated fibroblasts

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• 作者：Assunta Pisano ; Maria Francesca Santolla ; Ernestina Marianna De Francesco ; Paola De Marco ; Damiano Cosimo Rigiracciolo ; Maria Grazia Perri ; Adele Vivacqua ; Sergio Abonante ; Anna Rita Cappello ; Vincenza Dolce ; Antonino Belfiore ; Marcello Maggiolini and Rosamaria Lappano
• 刊名：Molecular Carcinogenesis
• 出版年：2017
• 出版时间：February 2017
• 年：2017
• 卷：56
• 期：2
• 页码：580-593
• 全文大小：2336K
• ISSN：1098-2744

文摘

Zinc (Zn) is an essential trace mineral that contributes to the regulation of several cellular functions; however, it may be also implicated in the progression of breast cancer through different mechanisms. It has been largely reported that the classical estrogen receptor (ER), as well as the G protein estrogen receptor (GPER, previously known as GPR30) can exert a main role in the development of breast tumors. In the present study, we demonstrate that zinc chloride (ZnCl₂) involves GPER in the activation of insulin-like growth factor receptor I (IGF-IR)/epidermal growth factor receptor (EGFR)-mediated signaling, which in turn triggers downstream pathways like ERK and AKT in breast cancer cells, and main components of the tumor microenvironment namely cancer-associated fibroblasts (CAFs). Further corroborating these findings, ZnCl₂ stimulates a functional crosstalk of GPER with IGF-IR and EGFR toward the transcription of diverse GPER target genes. Then, we show that GPER contributes to the stimulatory effects induced by ZnCl₂ on cell-cycle progression, proliferation, and migration of breast cancer cells as well as migration of CAFs. Together, our data provide novel insights into the molecular mechanisms through which zinc may exert stimulatory effects in breast cancer cells and CAFs toward tumor progression.