Breast cancer kills millions of women worldwide and thus it is critically important that current therapies are improved. As cancer is caused by a loss of normal cell-fate control, understanding how fate is regulated in normal and cancer cells will help to identify new therapeutic possibilities. Runx2 is critical for bone development, but its role in other tissues is not known. We used mammary gland transplants, conditional-knockouts and a mouse tumour model to determine Runx2 function in breast development and cancer in vivo. We further interrogated the role of Runx2 in normal epithelia and cancer cells by manipulating Runx2 levels in culture systems.
We discovered that Runx2-deficient mammary glands exhibited a developmental delay during pregnancy and had fewer luminal epithelial progenitors than wild-type controls (p<0.05). Moreover, Runx2 over-expression blocked differentiation in vitro by potentially maintaining the cells in a more progenitor-like state. These data suggest that Runx2 is required during pregnancy to regulate specification of progenitor cells, but Runx2 expression must then decrease in order for differentiation to occur. Forced expression of Runx2 in normal mammary epithelial cells drove EMT-like changes, while Runx2 inhibition reduced migration of aggressive breast cancer cell lines, where Runx2 levels are highest. In the mouse PyMT breast cancer model, Runx2-deficient tumours exhibited reduced proliferation and mice lived significantly longer than controls. Conversely, in a Runx2 transgenic model, mammary epithelial-specific Runx2 expression accelerated PyMT-driven tumorigenesis and promoted metastasis. Together, our data suggest that Runx2 inhibition may provide a route for therapeutic intervention in breast cancer to prolong patient survival.