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

  • Cancers (Basel). 2023 Aug 29;15(17):4320. doi: 10.3390/cancers15174320.
Ximena Bustamante-Marin  1  2 ,  Kaylyn L Devlin  3 ,  Shannon B McDonell  1 ,  Om Dave  1 ,  Jenna L Merlino  1 ,  Emma J Grindstaff  1 ,  Alyssa N Ho  1  2 ,  Erika T Rezeli  1 ,  Michael F Coleman  1  2 ,  Stephen D Hursting  1  2  4
Affiliations
  • 1. Department of Nutrition, University of North Carolina, Chapel Hill, NC 27599, USA.
  • 2. Nutrition Research Institute, University of North Carolina, Chapel Hill, NC 28081, USA.
  • 3. School of Medicine, Oregon Health and Science University, Portland, OR 97239, USA.
  • 4. Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.
PMID: 37686596 DOI: 10.3390/cancers15174320
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.

Keywords
IGF1R signaling; breast cancer; calorie restriction; miR-15b; triple-negative breast cancer.
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