The miR-424(322)/503 cluster orchestrates remodeling of the epithelium in the involuting mammary gland

Llobet-Navas D, Rodríguez-Barrueco R, Castro V, Ugalde AP, Sumazin P, Jacob-Sendler D, Demircan B, Castillo-Martín M, Putcha P, Marshall N, Villagrasa P, Chan J, Sanchez-Garcia F, Pe\\\'er D, Rabadán R, Iavarone A, Cordón-Cardó C, Califano A, López-Otín C, Ezhkova E, Silva JM.
Source: Genes Dev
Publication Date: (2014)
Issue: 28(7): 765-82
Research Area:
Basic Research
Cells used in publication:
Epithelial, mammary, human (HMEC)
Species: human
Tissue Origin: breast
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. Through the generation of a knockout 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 BCL-2 and IGF1R (insulin growth factor-1 receptor). Furthermore, we demonstrate that the expression of this microRNA cluster is regulated by TGF-ß, a well-characterized regulator of mammary involution. Overall, our data suggest a model in which activation of the TGF-ß pathway after weaning induces the transcription of miR-424(322)/503, which in turn down-regulates 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.