Mammary morphogenesis is orchestrated with other reproductive events by pituitary-driven changes to the systemic hormone environment, initiating the formation of a mammary ductal network during puberty and the addition of secretory alveoli during pregnancy. Prolactin is the major driver of development during pregnancy via regulation of ovarian progesterone production (in many species) and direct effects on mammary epithelial cells (in all species). Together these hormones regulate two aspects of development that are the subject of intense interest: (1) a genomic regulatory network that integrates many additional spatial and temporal cues to control gene expression and (2), the activity of a stem and progenitor cell hierarchy. Amalgamation of these two aspects will increase our understanding of cell proliferation and differentiation within the mammary gland, with clear application to our attempts to control breast cancer. Here we focus on providing an over-view of prolactin action during development of the model murine mammary gland.

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. Ó2014 AACR.

<p>Supplementary Data File containing: Supplementary Figure 1 - Failed lobuloalveolar development in Runx2 knockout transplanted mammary glands is retained at the first day postpartum. Supplementary Figure 2 - Generation and validation of Runx2 floxed;MMTV-cre mice. Supplementary Figure 3 - Runx2 floxed;MMTV-cre mice exhibit slightly delayed ductal elongation during puberty. Supplementary Figure 4 - Runx2 regulates luminal progenitor populations in Runx2 knockout transplanted mammary glands. Supplementary Figure 5 - Forced Runx2 expression does not perturb prolactin induced Stat5 activation in HC11 cells.</p>

<p>Supplementary Data File containing: Supplementary Figure 1 - Failed lobuloalveolar development in Runx2 knockout transplanted mammary glands is retained at the first day postpartum. Supplementary Figure 2 - Generation and validation of Runx2 floxed;MMTV-cre mice. Supplementary Figure 3 - Runx2 floxed;MMTV-cre mice exhibit slightly delayed ductal elongation during puberty. Supplementary Figure 4 - Runx2 regulates luminal progenitor populations in Runx2 knockout transplanted mammary glands. Supplementary Figure 5 - Forced Runx2 expression does not perturb prolactin induced Stat5 activation in HC11 cells.</p>