Authors:
Xiaoyang Wang, Yuzhi Yin, Hongyan Yuan, Toshiyuki Sakamaki, Robert I. Glazer
Summary:
The RNA-binding protein Musashi1 (Msi1) is a positive regulator of Notch-mediated transcription in Drosophila and neural progenitor cells, and has been recently identified as a putative human breast stem cell marker. Here we describe a functional role for Msi1 in stimulating proliferation within the mammary terminal end buds to drive expansion of progenitor cells along the luminal and myoepithelial lineages. Retroviral expression of Msi1 in mouse mammary epithelial cell line COMMA-1D increased cell proliferation that was associated with increased secretion of the growth factor, proliferin (PLF) and reduced secretion of the Wnt pathway inhibitor, Dickkopf-3 (DKK3). Stimulation of control cells with conditioned medium from Msi1-expressing cells increased colony formation and phosphoERK activity, whereas removal of PLF with a monoclonal antibody or treatment with the MEK inhibitor, U0126, inhibited ERK activation. Msi1 expression was associated with expansion of CD24hi/Sca-1+, CD24hi/CD24+, CK19, CK6 and double-positive CK14/CK18 progenitor cells. Engraftment of COMMA/Msi1 cells into the prepubertal cleared fat pad resulted in alveolar hyperplasia. Msi1 expression was also associated with increased Notch and β-catenin/TCF reporter activity, which was inhibited by U0126, as well as increased nuclear localization of β-catenin and increased transcription of Delta1 and Hes1. Additionally, Msi1 programmed the expression of a number of genes that have a concerted effect on the cell cycle, development and cell adhesion. Together, these studies identify Msi1 as a key determinant of mammary lineage through it ability to coordinate cell cycle entry and activation of the Notch and Wnt pathways.
Source:
American Association for Cancer Research Annual Meeting, (04/14/08)