Cellular Senescene and Breast Cancer

Abstract : Aging is the single largest risk factor for developing breast cancer and is thought to be due the convergence of the accumulation of mutations together with the accumulation of senescent cells. Our working hypothesis is that senescent epithelial cells can cause preneoplastic or neoplastic changes in its neighbors, and that these changes will be manifest when cells are cultured in three dimensions, which more closely mimics the natural tissue environment than conventional two dimensional cultures. To test this hypothesis, we have successfully established two and three dimensional culture models of normal human mammary epithelial cells (HMECs) with and without a functional 16-tumor suppressor pathway. We have also created preneoplastic HMECs by introducing defined genes with oncogenic potential, particularly genes that selectively inactivate the p53 or pRB tumor suppressor pathways. We have used these, and frankly neoplastic human mammary epithelial cells, in the two and three dimensional co-culture assays in which presenescent HMECs are mixed with senescent HMECs and stromal breast fibroblasts. We have devised ways to analyze factors secreted by senescent cells and compared human mammary epithelial cells with their stromal counterparts.