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Cancer Res. 2014 Sep 15;74(18):5277-5286. doi: 10.1158/0008-5472.CAN-14-0053. Epub 2014 Jul 23.

Runx2 is a novel regulator of mammary epithelial cell fate in development and breast cancer.

Author information

1
Discipline of Physiology & Bosch Institute, School of Medical Sciences, The University of Sydney, NSW 2006, Australia.
2
Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia.
3
The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.
4
Department of Medical Biology, University of Melbourne, Victoria 3052, Australia.
5
Faculty of Life Sciences, University of Manchester, Manchester, M13 9PT, UK.
6
St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, NSW 2052, Australia.
7
The University of Queensland, UQ Centre for Clinical Research (UQCCR), Herston, Queensland 4029, Australia.
8
Cancer Research UK, Cambridge Research Institute, Cambridge, CB2 0RE, UK.
#
Contributed equally

Abstract

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. Cancer Res; 74(18); 5277-86.

PMID:
25056120
PMCID:
PMC4178131
DOI:
10.1158/0008-5472.CAN-14-0053
[Indexed for MEDLINE]
Free PMC Article

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