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. In this second progress report, we demonstrate that transformed MSC with reduced DNA repair contribute to more aggressive mammary tumors. Transformed luminal progenitor cells with altered histone methylation produce aggressive mammary tumors after long latency. The fractions of progenitor and differentiated cells in these tumors also are altered. We show that ER+ tumor cells promote proliferation and metastasis of tumor derived MSCs. The implications of the results presented in this progress report suggest that while tumor suppressor pathways can inhibit mammary tumorigenesis when DNA damage repair is inhibited, more aggressive clones may eventually evolve via genomic instability with the ability to proliferate and metastasize. Decreased DNA damage repair or altered epigenetic marks can dramatically affect the cellular composition of these tumors, thereby regulating clinical phenotype. Paracrine factors secreted by ER+ tumor cells can induce proliferation of tumorigenic MSC, leading to increased genomic instability and metastasis.
Document Details
- Document Type
- Technical Report
- Publication Date
- Mar 01, 2012
- Accession Number
- ADA560890
Entities
People
- David L Crowe
Organizations
- University of Illinois at Chicago