Loss of cyclin D1 in concert with deregulated estrogen receptor alpha expression induces a DNA damage response and interrupts mammary gland morphogenesis Free

A108

Although cyclin D1 is not required for pubertal mammary gland development, introduction of deregulated and increased Estrogen Receptor alpha (ERα)expression in the mammary gland in concert with cyclin D1 deficiency resulted in upregulation of cyclin E and DNA damage checkpoint activation leading to p53-dependent apoptosis. Proliferative rates were dramatically reduced indicating that loss of cyclin D1 in conjunction with deregulation of ERα resulted in a novel and absolute dependency upon cyclin D1 for mammary epithelial cell proliferation. Thus, an imbalance between proliferative and apoptotic rates in conjunction with remarkable structural defects in the terminal end buds interrupted ductal morphogenesis. Interestingly, the structure of the mammary fat pad was fundamentally altered by the consequences of overexpressing ERα in the epithelial cells in the absence of cyclin D1 illustrating how alterations in the epithelial compartment can impact surrounding stromal composition. Transplantation of embryonic ERα-overexpressing and cyclin D1-deficient mammary epithelium into the cleared fat pad of wild type mice did not rescue the aberrant phenotype indicating that it was intrinsic to the mammary epithelial cells. In conclusion, although cyclin D1 is dispensable for proliferation of normal mammary epithelial cells, absence of cyclin D1 in abnormal ERα-overexpressing epithelial cells interrupted proliferation and led to apoptosis. These results demonstrate that normal and abnormal mammary epithelial cells can have differential sensitivity to loss of cyclin D1 and support the application of cyclin D1 inhibitors as therapeutic interventions. Our studies suggest that ERα-overexpressing breast cancers are good candidates for anti-cyclin D1 therapy.