Progenitor Cell Fate Decisions in Mammary Tumorigenesis.

摘要

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. We previously reported that transformed MSC with reduced DNA repair contribute to more aggressive mammary tumors. Transformed luminal progenitor cells with altered histone methylation produced aggressive mammary tumors after long latency. The fractions of progenitor and differentiated cells in these tumors also were altered. ER+ tumor cells promoted proliferation and metastasis of tumor derived MSC. H3K27me3 levels were increased in JMJD3 depleted ER+tumor cells. Tumors derived from MMTV-Wnt1 MSC co-transplanted with JMJD3 shRNA transduced ER+ cells demonstrated increased latency with decreased tumor number, volume, and metastasis. Tumors derived from MMTV-Wnt1 MSC co-transplanted with JMJD3 shRNA transduced ER+ cells were classified as poorly differentiated adenocarcinoma by histopathologic analysis. The MSC fraction was reduced in tumors containing JMJD3 shRNA transduced ER+ cells compared to control transduced tumors. The implications of the results presented in this 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 phenotype and outcomes. Paracrine factors secreted by ER+ tumor cells can induce proliferation of tumorigenic MSC, leading to increased genomic instability and metastasis. Epigenetic marks in specific tumor cell populations (MSC vs. ER+) can dramatically alter tumor phenotype and outcome.