I have been involved in various aspects of cancer research for my entire 40 year career in science; beginning with graduate school where I was a student with Dr. Mario Capecchi, and my post-doctoral fellowship with Dr. George Stark. Since that time, I have focused my lab’s efforts on identifying the molecules and mechanisms involved in the genetic and phenotypic heterogeneity common to most human cancers. Our work has involved uncovering the mechanisms that lead to the most common forms of genetic instability in human cancers. This led us to investigate the mechanisms that prevent normal cells from acquiring the large-scale chromosomal changes that fuel the progression of many cancers. This work revealed that one function of the p53 tumor suppressor, one of the most commonly mutated genes in human cancer, is to prevent the emergence and proliferation of cells with genome instability. However, we have also recognized that in some cancers, such as pancreatic cancer, there is substantial proliferation of an abnormal stroma that augments the growth of the associated epithelial cancer cells, and that this stroma has normal p53 that can be activated. We are currently working on strategies to activate the p53 in the abnormal stroma and see with this also impedes growth of co-cultured pancreatic cancer cells or decreases the stromal response in vivo. More recently, we showed that p53 can also limit the ability of normal cells to de-differentiate into pluripotent stem cells, and that its mutation in cancer correlates with the acquisition of a de-differentiated stem-like state associated with some of the most aggressive forms of breast cancer. Most recently, we have become interested in the nature of the stem-like cells in a dangerous form of very aggressive breast cancers referred to as “triple negative” because they lack or have low expression of estrogen and progesterone receptors and the Her2 protein, which encodes an epidermal growth factor related receptor. We identified, isolated and characterized the stem cells that are formed in the fetus. The genes expressed in these fetal mammary stem cells show significant similarities to those expressed in the triple negative breast cancers. We are now characterizing these cells further in an attempt to identify molecular targets for which non-genotoxic therapeutics can be developed to provide an alternative, or addition, to the chemotherapy currently used to treat patients whose cancers show an enrichment for the fetal mammary stem cell signature.