The effects of calorie restriction on mammary tumorigenesis via modulation of microRNAs

Devlin, Kaylyn L.
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Breast cancer is the most common cancer among US women, excluding skin cancer, and much effort has been directed toward the development of prevention and treatment strategies. Calorie restriction (CR) is a dietary intervention that has potent anticancer effects in preclinical animal models of breast cancer. The mechanisms behind the protective effects of CR are under investigation, although the influence of CR on the regulation of microRNAs (miRNAs), small RNA species that ubiquitously act as post-transcriptional regulators of gene expression, in the context of breast cancer has not been extensively explored. Due to the established inhibitory effects of CR on breast cancer progression and the recognized dysregulation of miRNAs as a result and contributing factor of tumorigenesis, I hypothesized that CR would alter miRNA expression, both at the individual and global levels, and that this modulation would contribute to the inhibition of mammary tumorigenesis observed with CR. Caloric restriction studies were conducted in rodent models of luminal and basal-like breast cancer and miRNA expression changes and resultant effects on tumorigenesis were analyzed. In the context of luminal cancer, CR normalized the expression of miR-200a, a miRNA positively-associated with progression, in mammary tumors. Inhibition of miR-200a function, mimicking CR’s effect on this miRNA, reduced mammary cancer cell proliferation. In basal-like cancer, CR was found to dually inhibit insulin-like growth factor-1 (IGF-1) signaling through the reduction of circulating substrate and the resultant upregulation of miR-15b, which targets IGF-1 receptor (IGF-1R) and reduced its expression. Overexpression of miR-15b subsequently inhibited mammary cancer cell proliferation. Furthermore, CR was found to affect global miRNA expression, by broadly upregulating miRNA expression in luminal mammary tumors, where miRNAs are commonly downregulated. This broad upregulation was associated with an increase in Dicer expression. Due to the challenges associated with the wide application of CR over the course of a lifetime, increasing interest is developing for the use of CR mimetics. The CR mimetics, metformin and rapamycin, were found to modulate the expression of distinct miRNAs in murine pancreatic tumors, suggesting that the protective effects of CR against tumorigenesis through miRNA regulation could be pharmacologically mimicked.