期刊
CANCER RESEARCH
卷 74, 期 18, 页码 5277-5286出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-14-0053
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资金
- Australian National Health and Medical Research Council (NHMRC)
- Cancer Council NSW
- Australian Research Council
- Victorian State Government through the Victorian Breast Cancer Research Consortium and Operational Infrastructure Support
- Australian Cancer Research Foundation
- NHMRC Career Development Fellowships
- National Breast Cancer Foundation of Australia Fellowships
- NHMRC [1017256]
- NHMRC Research Fellowship
- NHMRC Australia Fellowship
- Cancer Research UK [15602] Funding Source: researchfish
- National Breast Cancer Foundation [NC-12-24] Funding Source: researchfish
Regulators of differentiated cell fate can offer targets for managing cancer development and progression. Here, we identify Runx2 as a new regulator of epithelial cell fate in mammary gland development and breast cancer. Runx2 is expressed in the epithelium of pregnant mice in a strict temporally and hormonally regulated manner. During pregnancy, Runx2 genetic deletion impaired alveolar differentiation in a manner that disrupted alveolar progenitor cell populations. Conversely, exogenous transgenic expression of Runx2 in mammary epithelial cells blocked milk production, suggesting that the decrease in endogenous Runx2 observed late in pregnancy is necessary for full differentiation. In addition, overexpression of Runx2 drove epithelial-to-mesenchymal transition-like changes in normal mammary epithelial cells, whereas Runx2 deletion in basal breast cancer cells inhibited cellular phenotypes associated with tumorigenesis. Notably, loss of Runx2 expression increased tumor latency and enhanced overall survival in a mouse model of breast cancer, with Runx2-deficient tumors exhibiting reduced cell proliferation. Together, our results establish a previously unreported function for Runx2 in breast cancer that may offer a novel generalized route for therapeutic interventions. (C) 2014 AACR.
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