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Paola De Marco Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende (CS), Italy

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Enrica Romeo Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende (CS), Italy

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Adele Vivacqua Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende (CS), Italy

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Roberta Malaguarnera Endocrinology, Department of Health, University Magna Graecia of Catanzaro, Catanzaro, Italy

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Sergio Abonante Regional Hospital, Cosenza, Italy

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Francesco Romeo Regional Hospital, Cosenza, Italy

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Vincenzo Pezzi Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende (CS), Italy

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Antonino Belfiore Endocrinology, Department of Health, University Magna Graecia of Catanzaro, Catanzaro, Italy

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Marcello Maggiolini Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende (CS), Italy

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Paola De Marco
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Enrica Romeo
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Adele Vivacqua
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Roberta Malaguarnera Department of Pharmacy Health and Nutritional Sciences, University of Calabria, 87036 Rende (CS), Italy

Regional Hospital Cosenza, Italy

Endocrinology Department of Health, University Magna Graecia of Catanzaro, Catanzaro, Italy

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Sergio Abonante Department of Pharmacy Health and Nutritional Sciences, University of Calabria, 87036 Rende (CS), Italy

Regional Hospital Cosenza, Italy

Endocrinology Department of Health, University Magna Graecia of Catanzaro, Catanzaro, Italy

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Francesco Romeo Department of Pharmacy Health and Nutritional Sciences, University of Calabria, 87036 Rende (CS), Italy

Regional Hospital Cosenza, Italy

Endocrinology Department of Health, University Magna Graecia of Catanzaro, Catanzaro, Italy

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Vincenzo Pezzi
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Antonino Belfiore Department of Pharmacy Health and Nutritional Sciences, University of Calabria, 87036 Rende (CS), Italy

Regional Hospital Cosenza, Italy

Endocrinology Department of Health, University Magna Graecia of Catanzaro, Catanzaro, Italy

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Marcello Maggiolini
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Elevated insulin levels have been associated with an increased cancer risk as well as with aggressive and metastatic cancer phenotypes characterized by a poor prognosis. Insulin stimulates the proliferation, migration, and invasiveness of cancer cells through diverse transduction pathways, including estrogen signaling. As G protein estrogen receptor 1 (GPER1) mediates rapid cell responses to estrogens, we evaluated the potential of insulin to regulate GPER1 expression and function in leiomyosarcoma cancer cells (SKUT-1) and breast cancer-associated fibroblasts (CAFs), which were used as a model system. We found that insulin transactivates the GPER1 promoter sequence and increases the mRNA and protein expression of GPER1 through the activation of the PRKCD/MAPK1/c-Fos/AP1 transduction pathway, as ascertained by means of specific pharmacological inhibitors and gene-silencing experiments. Moreover, cell migration triggered by insulin occurred through GPER1 and its main target gene CTGF, whereas the insulin-induced expression of GPER1 boosted cell-cycle progression and the glucose uptake stimulated by estrogens. Notably, a positive correlation between insulin serum levels and GPER1 expression was found in cancer fibroblasts obtained from breast cancer patients. Altogether, our data indicate that GPER1 may be included among the complex network of transduction signaling triggered by insulin that drives cells toward cancer progression.

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