Regulation of IGF1R by MicroRNA-15b Contributes to the Anticancer Effects of Calorie Restriction in a Murine C3-TAg Model of Triple-Negative Breast Cancer

SIMPLE SUMMARY: Breast cancer is the most common cancer in women worldwide. The risk of developing postmenopausal breast cancer is exacerbated by obesity (BMI > 30 kg/m(2)), and growing evidence suggests that obesity increases the risk of developing triple-negative breast cancer. Calorie restriction (CR), a reduction of calorie intake by 20–40% without causing malnutrition, is associated with decreasing an individual’s risk of developing cancer, enhancing the responses to cancer treatment, and reducing the risk of breast cancer recurrence. The negative impact of CR on breast cancer growth may result from lowering bioavailable levels of IGF1. In this study, we suggest that CR’s antitumor effects are partly mediated by the upregulation of miR-15b, which downregulates IGF1R and other target genes involved in cell cycle control. Our findings suggest that miR-15b could mediate CR’s regulation of IGF1/IGF1R signaling that contributes to the anticancer properties of this dietary intervention. ABSTRACT: Calorie restriction (CR) inhibits triple-negative breast cancer (TNBC) progression in several preclinical models in association with decreased insulin-like growth factor 1 (IGF1) signaling. To investigate the impact of CR on microRNAs (miRs) that target the IGF1/IGF1R pathway, we used the spontaneous murine model of TNBC, C3(1)/SV40 T-antigen (C3-TAg). In C3-TAg mice, CR reduced body weight, IGF1 levels, and TNBC progression. We evaluated the tumoral expression of 10 miRs. CR increased the expression of miR-199a-3p, miR-199a-5p, miR-486, and miR-15b. However, only miR-15b expression correlated with tumorigenicity in the M28, M6, and M6C C3-TAg cell lines of TNBC progression. Overexpressing miR-15b reduced the proliferation of mouse (M6) and human (MDA-MB-231) cell lines. Serum restriction alone or in combination with low levels of recombinant IGF1 significantly upregulated miR-15b expression and reduced Igf1r in M6 cells. These effects were reversed by the pharmacological inhibition of IGFR with BMS754807. In silico analysis using miR web tools predicted that miR-15b targets genes associated with IGF1/mTOR pathways and the cell cycle. Our findings suggest that CR in association with reduced IGF1 levels could upregulate miR-15b to downregulate Igf1r and contribute to the anticancer effects of CR. Thus, miR-15b may be a therapeutic target for mimicking the beneficial effects of CR against TNBC.