5 years ago

MiRNA-513a-5p Inhibits Progesterone Receptor Expression and Constitutes a Risk Factor For Breast Cancer: The ORDET Prospective Study.

S Strano, A Hossain, F Berrino, V Krogh, S Donzelli, S Sieri, A Sacconi, Y Yarden, J Beyene, F Biagioni, F Ganci, P Muti, G Blandino, T Frixa
MicroRNAs (miRNAs) might be considered both predictors and players of cancer development. The aim of the present report was to investigate whether many years before the diagnosis of breast cancer miRNA expression is already disregulated. In order to test this hypothesis we compared miRNAs extracted from leukocytes in healthy women who later developed breast cancer and in women who remain healthy during the whole fifteen-year follow-up time. Accordantly, we used a case-control study design nested in the ORDET prospective cohort study addressing the possibility that miRNAs can serve as both early biomarkers and components of the hormonal etiological pathways leading to breast cancer development in premenopausal women. We compared leukocyte miRNA profiles of 191 incident premenopausal breast cancer cases and profiles of 191 women who remained healthy over a follow-up period of 20 years. The analysis identified 20 differentially expressed miRNAs in women candidate to develop breast cancer versus control women. The up-regulated miRNAs, miR-513-a-5p, miR-513b-5p and miR-513c-5p were among the most significantly deregulated miRNAs. In multivariate analysis, miR-513a-5p up-regulation was directly and statistically significant associated with breast cancer risk (OR=1.69; 95% CI, 1.08 to 2.64; P=0.0293). In addition, the up-regulation of miR-513-a-5p displayed the strongest direct association with serum progesterone and testosterone levels. The experimental data corroborated the inhibitory function of miR-513a-5p on progesterone receptor expression confirming that progesterone receptor is a target of miR-513a-5p.The identification of up-regulated miR-513a-5p with its oncogenic potential further validates the use of miRNAs as long-term biomarker of breast cancer risk.

Publisher URL: http://doi.org/10.1093/carcin/bgx126

DOI: 10.1093/carcin/bgx126

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