The tamoxifen-dependent cytotoxic effects on cell proliferation were determined by MTT assay and clonogenic potential measurement. Methods: We used estrogen-dependent insulin-like growth factor receptor I deleted gene (MCF7 IGFIRKO) breast cancer cell models, lentivirally transduced to over-express empty-vector (MCF7 IGFIRKO/EV), IRA (MCF7 IGFIRKO/IRA) or IRB (MCF7 IGFIRKO/IRB), to investigate the role of insulin receptors on the antiproliferative activity of tamoxifen in presence of low and high glucose concentrations. While the role of Insulin-like growth factor receptor I in breast cancer progression and therapy resistance is well established, the effects of insulin receptors in this context are complex and not completely elucidated. Both classes of receptors show high homology and can initiate the intracellular signaling cascade alone or by hybrids formation. Insulin/Insulin-like growth factor signaling is triggered by two insulin receptor isoforms identified as IRA and IRB and by Insulin-like growth factor receptor I. Indeed, epidemiological and pre-clinical studies have shown its involvement in the development, progression, and therapy resistance of several cancer types including breast cancer. Insulin and Insulin-like growth factor signaling exert a mitogenic and pro-survival effect. Introduction: Breast cancer is the most common malignancy in women, and it is linked to several risk factors including genetic alterations, obesity, estrogen signaling, insulin levels, and glucose metabolism deregulation. 4University Oncology Department, Humanitas Istituto Clinico Catanese, Catania, Italy.3Division of Hematology, Azienda Ospedaliera Universitaria (A.O.U.) Policlinico “G.2Center of Experimental Oncology and Hematology, Azienda Ospedaliera Universitaria (A.O.U.) Policlinico “G.1Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy.Stefania Stella 1,2*†, Michele Massimino 1,2†, Livia Manzella 1,2†, Nunziatina Laura Parrinello 3, Silvia Rita Vitale 1,2, Federica Martorana 1,2 and Paolo Vigneri 1,2,4
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