The mammary gland is a very dynamic organ that undergoes continuous remodeling. The critical regulators of this process are not fully understood. Here we identify the microRNA cluster miR-424(322)/503 as an important regulator of epithelial involution after pregnancy and tumorigenesis. Importantly, miR-424(322)/503 loci is deleted in 20% of basal and luminal B tumors. Through the generation of a knock-out mouse model, we found that regression of the secretory acini of the mammary gland was compromised in the absence of miR-424(322)/503. Mechanistically, we show that miR-424(322)/503 orchestrates cell life and death decisions by targeting CDC25A, BCL-2 and IGF1R. Furthermore, we demonstrate that the expression of this miR-cluster is regulated by TGF-β, a well characterized regulator of mammary involution. Overall, our data suggest a model where activation of the TGF-β pathway after weaning induces the transcription of the miR-424(322)/503 which in turn downregulates the expression of key genes. Here, we unveil a previously unknown, multilayered-regulation of epithelial tissue remodeling coordinated by the microRNA cluster miR-424(322)/503.

Note: This abstract was not presented at the meeting.

Citation Format: David Llobet Navas, Ruth Rodriguez Barrueco, Jose Silva. miR-424(322)/503 cluster orchestrates remodeling of the epithelium in the involuting mammary gland and plays a role in breast cancer development. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5214. doi:10.1158/1538-7445.AM2014-5214