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Molecular and Cellular Biology, June 2008, p. 3589-3599, Vol. 28, No. 11
0270-7306/08/$08.00+0     doi:10.1128/MCB.00040-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Musashi1 Modulates Mammary Progenitor Cell Expansion through Proliferin-Mediated Activation of the Wnt and Notch Pathways ^,

Department of Oncology, Georgetown University, and Lombardi Comprehensive Cancer Center, Washington, DC 20007,¹ Niigata University, Niigata, Japan,² Keio University, Tokyo, Japan³

Received 9 January 2008/ Returned for modification 6 February 2008/ Accepted 13 March 2008

The RNA-binding protein Musashi1 (Msi1) is a positive regulator of Notch-mediated transcription in Drosophila melanogaster and neural progenitor cells and has been identified as a putative human breast stem cell marker. Here we describe a novel functional role for Msi1: its ability to drive progenitor cell expansion along the luminal and myoepithelial lineages. Expression of Msi1 in mammary epithelial cells increases the abundance of CD24^hi Sca-1⁺, CD24^hi CD29⁺, CK19, CK6, and double-positive CK14/CK18 progenitor cells. Proliferation is associated with increased proliferin-1 (PLF1) and reduced Dickkopf-3 (DKK3) secretion into the conditioned medium from Msi-expressing cells, which is associated with increased colony formation and extracellular signal-regulated kinase (ERK) phosphorylation. Treatment with the MEK inhibitor U0126 inhibits ERK activation and decreases Notch and β-catenin/T-cell factor (TCF) reporter activity resulting from Msi1 expression. Reduction of DKK3 in control cells with a short hairpin RNA (shRNA) increases Notch and β-catenin/TCF activation, whereas reduction of PLF1 with a shRNA in Msi1-expressing cells inhibits these pathways. These results identify Msi1 as a key determinant of the mammary lineage through its ability to coordinate cell cycle entry and activate the Notch and Wnt pathways by a novel autocrine process involving PLF1 and DKK3.

Published ahead of print on 24 March 2008.

Supplementary material for this article may be found at http://mcb.asm.org/.