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 reducedIgf1rin 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 downregulateIgf1rand contribute to the anticancer effects of CR. Thus, miR-15b may be a therapeutic target for mimicking the beneficial effects of CR against TNBC.
热量限制（CR）在多种临床前模型中能够抑制三阴性乳腺癌（TNBC）的进展，这一作用与胰岛素样生长因子1（IGF1）信号通路的减弱相关。为探究CR对靶向IGF1/IGF1R通路的微小RNA（miRs）的影响，我们采用了自发性小鼠TNBC模型C3(1)/SV40 T抗原（C3-TAg）。在C3-TAg小鼠中，CR降低了体重、IGF1水平并延缓了TNBC进展。我们评估了10种miRs在肿瘤中的表达情况，发现CR上调了miR-199a-3p、miR-199a-5p、miR-486和miR-15b的表达。然而，仅在TNBC进展相关的M28、M6和M6C C3-TAg细胞系中，miR-15b的表达与致瘤性呈相关性。过表达miR-15b可降低小鼠（M6）和人源（MDA-MB-231）细胞系的增殖能力。单独血清限制或联合低浓度重组IGF1处理能显著上调M6细胞中miR-15b的表达并降低Igf1r水平，而使用BMS754807药物抑制IGFR则可逆转这些效应。通过miR网络工具进行的生物信息学分析预测，miR-15b靶向与IGF1/mTOR通路及细胞周期相关的基因。我们的研究结果表明，CR伴随IGF1水平降低可能通过上调miR-15b来下调Igf1r，从而参与CR的抗癌效应。因此，miR-15b或可作为模拟CR对抗TNBC有益效应的治疗靶点。
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