Abstract B68: Calorie restriction normalizes global microRNA expression by preventing the loss of Dicer expression during mammary tumorigenesis

Abstract

MicroRNA (miRNAs) are small, post-transcriptional regulators that play an integral role in maintenance of cellular functions and whose dysregulation has been shown to promote many types of cancer, including breast cancer. Global downregulation of miRNAs has emerged as a common theme in human breast tumors and has been shown to contribute to oncogenesis. One of the primary mechanisms through which miRNAs are globally dysregulated is downregulation of enzymes involved in miRNA biogenesis. We aim to establish how calorie restriction (CR), which potently inhibits breast cancer progression, regulates global miRNA expression and the expression of miRNA biogenesis enzymes in mammary tumors. To address these questions, 100 female Sprague Dawley rats were administered either dimethylbenz(a)anthracene (DMBA) or vehicle control at 50 days of age, then randomized to receive either control (AIN-76A) diet ad-libitum (n=40) or a 30% CR diet regiment (n=60). Resultant mammary tumors were allowed to develop for 12 weeks. Calorie restriction significantly increased survival to study endpoint relative to control diet (75% vs 35%, respectively) (p=0.0047). Furthermore, of the animals that developed tumors, CR significantly decreased median tumor area by 56% compared to control diet (109.4 mm2 vs 250.9 mm2, respectively) (p=0.0286). Global miRNA expression was analyzed by miRNA-specific sequencing. Calorie restriction had a broad effect on miRNA expression, illustrated by the fact that of all the miRNAs with a greater than two-fold expression difference between CR and control, 80% are overexpressed in CR tumors compared to control tumors. These results can be explained by the additional finding that CR was able to prevent the loss of Dicer expression, a key miRNA biogenesis enzyme, observed in control-fed mammary tumor tissue compared to normal tissue. This important finding suggests that global miRNA normalization through the retention of Dicer expression during cancer progression could be a contributing mechanism to CR's anticancer effects. We are further investigating these findings by exogenously overexpressing Dicer in Rama25 cells (derived from a DMBA-induced mammary tumor in a Sprague Dawley rat) and MCF7 cells, and analyzing the resultant tumorigenic potential in vitro and in vivo. The results obtained will provide insights into the mechanisms of breast cancer progression and how CR inhibits progression through microRNA modulation.

Citation Format: Kaylyn L. Devlin, Tiffany Sanford, Elizabeth Mambo, Stephen D. Hursting. Calorie restriction normalizes global microRNA expression by preventing the loss of Dicer expression during mammary tumorigenesis. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr B68.