Abstract
Abstract BACKGROUND: A role for EZH2 in stem cell maintenance was recently reported. Our lab has previously demonstrated that overexpression of EZH2 accelerates the initiation of ErbB2-induced mammary tumors. To understand underlying mechanism, we investigated the role of EZH2 in regulation of stem cells and luminal progenitor cells utilizing xenotransplantation studies of preneoplastic mammary glands of EZH2+; neu and EZH2 wt; neu transgenic mice. METHODS: Generation of crossing EZH2+; neu and EZH2 wt; neu transgenic mice was described previously. Mouse handling and experimental procedures were conducted in accordance with the NIH Guide for the Care and Use of Laboratory Animals and were approved by the IACUC of the UM. Stem cells (Lin-/CD49f+/ESA-) and luminal progenitor cells (Lin-/CD49f+/ESA+) were isolated from the hyperplastic mammary glands of 8 weeks old EZH2+; neu and EZH2 wt; neu mice by flow cytometry (n=15 per group). Stem cells and luminal progenitor cells were injected into cleared fat pads of 3 weeks old FVB mice. After 5 weeks the mammary glands were subjected to flow cytometry and histology. RESULTS: Histologic study showed that only the stem cells, but not the luminal progenitor cells, extracted from EZH2+; neu and EZH2 wt; neu transgenic mice were able to form mammary outgrowths. Outgrowths of EZH2+;neu mice had significantly increased epithelial proliferation and increased numbers of terminal end buds (p<0.05) compared to EZH2 wt;neu outgrowths. EZH2 +;neu outgrowths had significant upregulation of Ki67 and pSTAT5 proteins. Flow cytometry of the outgrowths revealed that while all cell populations were increased, EZH2 induced a more pronounced expansion of the stem cell and luminal progenitor cell populations. CONCLUSIONS: Our data show that EZH2 overexpression in ErbB2 mice induces an expansion of the multipotent mammary stem cell population with the ability to regenerate the cellular heterogeneity of the mammary gland and develop hyperplastic outgrowths. We found that EZH2 promotes hyperproliferation and upregulation of STAT5 phosphorylation in the mammary epithelium in vivo. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5208. doi:1538-7445.AM2012-5208
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