Abstract P4-07-14: The effects of calorie restriction on microRNA expression profiles and DMBA-induced mammary tumorigenesis in a model of luminal A breast cancer

Abstract

Abstract MicroRNA (miR) are small, post-transcriptional regulators that play an integral role in maintenance of cellular functions and whose dyregulation has been shown to promote many types of cancer, including breast cancer. While it has been shown that microRNA are dyregulated through the stages of breast cancer development, it was our goal to define the microRNA expression profiles of the individual stages in a model of luminal A breast cancer in order to identify which are specifically associated with progression. In addition, we aim to establish the effects of calorie restriction, which is known to inhibit breast cancer progression, on relevant microRNA. To address these questions, 100 female Sprague Dawley rats were administered either dimethylbenz(a)anthracene 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). To analyze the impact of microRNA modulation on tumor progression, mammary tumors from control animals were microdissected in a stage-dependent fashion, with areas of normal epithelium, intraductal proliferation, ductal carcinoma in-situ, and invasive ductal carcinoma collected and analyzed separately. We have identified 10 microRNAs that are associated with cancer progression in this model (miR-10a, -10b, -21, -92b, -124, -125b, -126, -145, -200a, -658). We are currently analyzing which of these microRNAs are CR-responsive and how their modulation affects tumorigenic indices. The results obtained will provide insights into the mechanisms of breast cancer progression and how calorie restriction inhibits progression through microRNA modulation. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-07-14.