title: The miR-424(322)/503 cluster orchestrates remodeling of the epithelium in the involuting mammary gland.
abstract: 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-β, a well-characterized regulator of mammary involution. Overall, our data suggest a model in which activation of the TGF-β 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.
authors.affiliation: Institute for Cancer Genetics, Department of Pathology, Columbia University, New York, New York 10032, USA;
authors.forename: David
authors.initials: D
authors.lastname: Llobet-Navas
authors.forename: Ruth
authors.initials: R
authors.lastname: Rodríguez-Barrueco
authors.forename: Verónica
authors.initials: V
authors.lastname: Castro
authors.forename: Alejandro P
authors.initials: AP
authors.lastname: Ugalde
authors.forename: Pavel
authors.initials: P
authors.lastname: Sumazin
authors.forename: Damian
authors.initials: D
authors.lastname: Jacob-Sendler
authors.forename: Berna
authors.initials: B
authors.lastname: Demircan
authors.forename: Mireia
authors.initials: M
authors.lastname: Castillo-Martín
authors.forename: Preeti
authors.initials: P
authors.lastname: Putcha
authors.forename: Netonia
authors.initials: N
authors.lastname: Marshall
authors.forename: Patricia
authors.initials: P
authors.lastname: Villagrasa
authors.forename: Joseph
authors.initials: J
authors.lastname: Chan
authors.forename: Félix
authors.initials: F
authors.lastname: Sanchez-Garcia
authors.forename: Dana
authors.initials: D
authors.lastname: Pe'er
authors.forename: Raul
authors.initials: R
authors.lastname: Rabadán
authors.forename: Antonio
authors.initials: A
authors.lastname: Iavarone
authors.forename: Carlos
authors.initials: C
authors.lastname: Cordón-Cardó
authors.forename: Andrea
authors.initials: A
authors.lastname: Califano
authors.forename: Carlos
authors.initials: C
authors.lastname: López-Otín
authors.forename: Elena
authors.initials: E
authors.lastname: Ezhkova
authors.forename: Jose M
authors.initials: JM
authors.lastname: Silva
mesh_terms: D000818:Animals; D016923:Cell Death / Q000235:genetics; D002460:Cell Line; D004848:Epithelium / Q000378:metabolism*; D005260:Female; D018507:Gene Expression Regulation, Developmental; D055786:Gene Knockout Techniques; D006801:Humans; D008321:Mammary Glands, Animal / Q000166:cytology / Q000378:metabolism*; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014886:Weaning
chemical_list: C583176:MIRN424 microRNA, mouse; D035683:MicroRNAs; D019253:Proto-Oncogene Proteins c-bcl-2; D053773:Transforming Growth Factor beta1; D017526:Receptor, IGF Type 1
keywords: BCL2; IGF1R; TGFβ; mammary gland development; miR-424; miR-503