MICRO-RNA146B PROMOTES ALVEOLAR PROGENITOR CELL MAINTENANCE THROUGH PREFERENTIAL REGULATION OF STAT3B

Abstract

In this research, we have demonstrated that miRNA146b-5p (miR146b) is a hormonally regulated miRNA that participates in the maintenance of mammary alveolar progenitors during pregnancy and lactation by preferential regulation of STAT3B. Recently, our laboratory isolated distinct ductal, alveolar and multipotent mammary progenitors by single-cell cloning of the COMMA-D (CD) cell line. Molecular characterization of the distinct clones showed significantly higher expression of miR146b in the CD derived alveolar compared to the ductal and multipotent progenitors. Additionally, there was a significant rise in miR146b mRNA levels in the pregnant and lactating mouse mammary glands and in virgin glands following in vivo administration of estrogen and progesterone. An analysis of mammary epithelial subpopulations during pregnancy showed a significantly higher expression of miR146b in the alveolar luminal progenitors compared to stem and differentiated luminal cells. Induced knockdown of miR146b led to increased cell death in the CD derived alveolar progenitors and a significant reduction in the percentage of primary mouse mammary alveolar luminal progenitors. Among several of the candidate targets, miR146b regulated STAT3B and to a lesser extent STAT3A. A reporter construct using STAT3A 3'UTR inserted downstream of the firefly luciferase showed a significant reduction in reporter activity when cells overexpressed miR146b. As an imbalance in miR146b has been linked to human breast cancers, regulation of STAT3 isoforms may be a novel mechanism by which miR146b participates in breast carcinogenesis.