The Role of Stromal Fibroblast Hypoxic Response in Mammary Tumor Progression

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DESCRIPTION (provided by applicant): Dr. Randall Johnson is a distinguished scientist in the fields of breast cancer biology. Dr. Johnson lab has established a number of transgenic mouse models, which have been employed for the studies demonstrating the critical role of hypoxic (low oxygen tension) response in progression and pulmonary metastasis from mammary gland cancers(13, 16, 20, 25). Taking advantage of these available resources as well as Dr. Johnson's scientific guidance, training in Johnson lab will provide me an ideal opportunity to obtain experience of utilizing animal models, which will complement my previous research experience in the cellular and biochemical analysis of cancer progression. I believe that training in Johnson lab and my determined goal to become a good scientist will synergistically construct an infrastructure for my research career as an independent cancer biologist. A cancer cell is dependent on its microenvironment. The tumor microenvironment is the host microenvironment in which cancer cells originate, multiply and spread. Recent studies have shown that the tumor microenvironment plays a pivotal role in a cancer cell's growth, malignant progression and metastasis(22). However, little is known about the characteristics of the tumor microenvironment, and how a cancer cell interacts with its microenvironment. Fibroblasts (supporting cells) are key components of the tumor microenvironment. Fibroblasts have been shown to accelerate breast cancer growth and metastatic spread(6, 24). However, the molecular mechanism underlying the role of fibroblasts in the promotion of tumor growth and metastasis is poorly understood. Hypoxia, or a shortage of oxygen, is another prominent element in the tumor microenvironment(26). The formation of hypoxic regions results from the insufficient blood vessel formation that then leads to inadequate blood perfusion to rapidly growing tumors. In hypoxic cancer tissue, the hypoxia- inducible factor-1 (HIF-1), a hypoxia-responsive protein that is essential for hypoxic adaptation of tumors has been found to be overexpressed and to contribute to tumor progression(23, 25). Yet, how hypoxia and HIF-1 expression affect fibroblasts in mammary tumors, and most importantly how this contributes to the progression of breast cancer, have not been studied. This study will take advantage of genetically engineered mouse models, in which the HIF-1a gene is specifically ablated in fibroblasts in conjunction with MMTV-PyMT transgenic mice that develop breast cancer in the mammary glands(19). We propose experiments that will test the hypothesis that HIF-1 expression in fibroblasts plays a pivotal role in the breast cancer progression and metastatic spread by generating a more supportive microenvironment for tumor progression. Our research plan proposed here may reveal potential molecular implications of tumor-associated fibroblasts in the hypoxic microenvironment of tumors during breast cancer progression. PUBLIC HEALTH RELEVANCE: Research plan proposed here will determine how tumor-associated fibroblasts, a prominent host component of tumor microenvironment affect breast cancer progression. This will provide insight into potentials for targeting cross-communication between cancer cells and their microenvironment, which may be exploited for more effective therapeutic tactics in treating breast cancer.