Runx2 Is a Novel Regulator of Mammary Epithelial Cell Fate in Development and Breast Cancer

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. Ó2014 AACR.

Hormone-Sensing Mammary Epithelial Progenitors: Emerging Identity and Hormonal Regulation

“…In contrast to RUNX1, RUNX2 is found most highly expressed in mouse basal MECs, with expression detected in both basal and luminal lineages [156,157]. The expression of RUNX2 is negatively correlated with ERα expression, and this has been implicated as a mechanism by which ERα promotes maintenance of a differentiated epithelial phenotype by antagonising the EMT-inducing effect of RUNX2 [158].…”

“…The expression of RUNX2 is negatively correlated with ERα expression, and this has been implicated as a mechanism by which ERα promotes maintenance of a differentiated epithelial phenotype by antagonising the EMT-inducing effect of RUNX2 [158]. Transplantation of Runx2-/-mouse mammary buds into immunocompromised recipient mouse fat pads demonstrated that RUNX2 is not required for mammary outgrowth but Runx2-/-outgrowths exhibit defective alveologenesis during late pregnancy (>18 days post coitum- [157]). The lack of defective outgrowth in Runx2 knockout mice but inhibited lobuloalveolar differentiation also suggests a greater integration of RUNX with the actions of progesterone rather than those of oestrogen.…”

Runx2 expression: A mesenchymal stem marker for cancer

“…Epithelial-mesenchymal transition (EMT) is involved in carcinogenesis and promotes metastatic spreading (13)(14)(15). Following its recognition as a regulator gene in transformed epithelial cells in breast, lung and thyroid carcinoma (13)(14)(15), it has been suggested that Runx2 may promote breast cancer metastasis by EMT (13).…”

“…Following its recognition as a regulator gene in transformed epithelial cells in breast, lung and thyroid carcinoma (13)(14)(15), it has been suggested that Runx2 may promote breast cancer metastasis by EMT (13). The cancer caused by EMT is a consequence of complicated reprogramming process involving differentiation, epigenetics and metabolic balance disruption (16).…”

“…The cancer caused by EMT is a consequence of complicated reprogramming process involving differentiation, epigenetics and metabolic balance disruption (16). In this scenario, Runx2 has been identified as a regulator gene of transformed epithelial cells in breast, lung and thyroid carcinoma (13)(14)(15), and it has been suggested that this gene promotes breast cancer metastasis via EMT (13).…”