title: GPER, IGF-IR, and EGFR transduction signaling are involved in stimulatory effects of zinc in breast cancer cells and cancer-associated fibroblasts.
abstract: 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, ZnCl2stimulates 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 ZnCl2on 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. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy.
authors.forename: Assunta
authors.initials: A
authors.lastname: Pisano
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy.
authors.forename: Maria Francesca
authors.initials: MF
authors.lastname: Santolla
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy.
authors.forename: Ernestina Marianna
authors.initials: EM
authors.lastname: De Francesco
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: De Marco
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy.
authors.forename: Damiano Cosimo
authors.initials: DC
authors.lastname: Rigiracciolo
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy.
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Perri
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy.
authors.forename: Adele
authors.initials: A
authors.lastname: Vivacqua
authors.affiliation: Breast Cancer Unit, Regional Hospital, Cosanza, Italy.
authors.forename: Sergio
authors.initials: S
authors.lastname: Abonante
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy.
authors.forename: Anna Rita
authors.initials: AR
authors.lastname: Cappello
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy.
authors.forename: Vincenza
authors.initials: V
authors.lastname: Dolce
authors.affiliation: Division of Endocrinology, Department of Health, University Magna Graecia of Catanzaro, Catanzaro, Italy.
authors.forename: Antonino
authors.initials: A
authors.lastname: Belfiore
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy.
authors.forename: Marcello
authors.initials: M
authors.lastname: Maggiolini
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy.
authors.forename: Rosamaria
authors.initials: R
authors.lastname: Lappano
mesh_terms: D001940:Breast / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D000072645:Cancer-Associated Fibroblasts / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002712:Chlorides / Q000378:metabolism*; D018450:Disease Progression; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D006801:Humans; D011960:Receptors, Estrogen / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D017451:Receptors, Somatomedin / Q000378:metabolism*; D015398:Signal Transduction; D017967:Zinc Compounds / Q000378:metabolism*
chemical_list: D002712:Chlorides; C109584:GPER1 protein, human; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; D017451:Receptors, Somatomedin; D017967:Zinc Compounds; C016837:zinc chloride; D066246:ErbB Receptors
keywords: EGFR; GPER; IGF-IR; breast cancer cells; cancer-associated fibroblasts; zinc