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Aged Stroma in Breast Tumorigenesis: Development of an In Vivo Model
Tumor Cell Biology II
The single largest risk factor for the development of neoplasia, including breast cancer, is age. Cellular transformation and the subsequent development of a neoplasia is the result of a stepwise process in which an incipient cancer cell evolves from a normal cell into a fully transformed cell capable of invasion and metastasis. While it is clear that these cell autonomous changes are integral to the transformation process, it has become evident that changes in the surrounding stroma are also critical. Indeed, nontumorigenic fibroblasts within a tumor are capable of secreting factors that promote tumor cell growth. Similarly, senescent fibroblasts can promote tumor growth in xenograft models. Like genetic mutations, senescent fibroblasts accumulate as an organism ages. Because the secretory profile of a senescent cell differs from its younger counterpart, it is possible that the increased presence of senescent cells alters tissue architecture and plays a pivotal role in tumorigenicity. The goal of this study is to develop a murine model in which we can conditionally activate senescence in the stroma of a mouse and determine whether this premature ?aging? increases the incidence of breast carcinogenesis. The specific aims are: 1) development and characterization of conditional senescent mice and 2) determine whether senescent stroma enhances tumor incidence in well-defined breast tumor models. We have already created transgenic mice in which Cre recombinase can activate a GFP-ARF fusion gene (ectopic expression of ARF induces senescence and cells that undergo this type of senescence are able to stimulate the growth of preneoplastic cells). We propose to mate these mice to ones in which a Cre-estrogen receptor (Cre-ER) fusion protein is expressed specifically in fibroblasts (we already possess these mice through our collaboration with Dr. XXXXXX). The compound mice (expressing fibroblast specific Cre-ER and a conditional GFP-ARF protein) will then be mated with tumor prone models including MMTV-Her/Neu and MMTV-PyMT and tumor incidence and latency will be assessed. We predict that the activation of senescence in these models will increase tumor incidence and decrease latency. These studies will allow us to more accurately model the physiology of tumor formation and progression and have important implications in our understanding of breast carcinogenesis and may reveal novel anti-neoplastic targets.
Numerous risk factors predispose a woman to develop breast cancer. The greatest of these risk factors is age; raising the question of what about age predisposes a person to breast cancer. One answer to this question comes from the cancer cell itself. The development of breast cancer is a stepwise process whereby a pre-cancerous cell undergoes several genetic changes. These mutations take time to accumulate. A second reason for the increased chance of developing breast cancer with age might come from cells that surround the cell that will one day be cancerous. Indeed, recent studies suggest that the normal surrounding cells (those that do not obtain genetic changes and do not become tumor cells) play an important role in the development of cancer. Recently it was shown that when "old" cells are mixed with pre-cancerous cells they promote tumor formation (the same is not true when "young" cells are mixed with pre-cancerous cells). This suggests that "old" cells have undergone changes that allow them to promote cancer. Because both pre-cancerous and "old" cells accumulate with age, it raises the possibility that the increased tumor incidence observed in older women is influenced by both the accumulation of genetic changes in pre-cancerous cells and "old" cells throughout an individual's lifetime. As these two cell types accumulate, the probability that they will encounter each other increases, eventually resulting in tumor formation. Currently no animal models exist to test the role of "old" cells in the development of breast cancer. The focus of this study is to develop a mouse model in which we can prematurely induce "aged" cells and test whether this leads to an increased chance to develop breast cancer. If successful, this model will provide an ideal animal in which to identify novel anti-cancer targets and test their ability to inhibit breast cancer formation. Importantly, these new targets will be focused on normal cells, which are less likely to develop resistance, which is commonly associated with classic chemotherapy agents employed to battle breast cancer.