Progenitor Cell Fate Decisions in Mammary Tumorigenesis
Abstract
We proposed that alterations in histone methylation regulate MSC fate commitment and predispose these progeny to malignant transformation. Transformed ER+ epithelial cells deregulate proliferation of MSC and luminal progenitors contributing to transformation of ER- luminal and basal cells and development of treatment resistant breast cancer. Specific Aim #1 tested the hypothesis that EZH2 regulates both ER and DNA repair gene expression in MSC resulting in the differentiation of ER+ but transformation sensitive mammary epithelial cells. Our preliminary results indicate that inhibiting EZH2 expression in luminal progenitor cells significantly reduced histone H3K27me3 levels. These epigenetic changes increased DNA repair activity in luminal progenitor cells. DNA repair was significantly inhibited in MSC transduced with Rad50 and NBS1 shRNAs. Transplanted MSC with reduced Rad50 or NBS1 expression but not EZH2 inhibited luminal progenitors reconstituted mammary fat pads.
Document Details
- Document Type
- Technical Report
- Publication Date
- Mar 01, 2011
- Accession Number
- ADA542770
Entities
People
- David L Crowe
Organizations
- University of Illinois at Chicago