Linda deGraffenried - US grants

DESCRIPTION (provided by applicant): Prostate cancer is the most common non-skin cancer among men in most western populations, and it is the second leading cause of cancer death among U.S. men. Despite its high morbidity, the etiology of prostate cancer remains largely unknown. Epidemiological studies have established advancing age, race, and a family history of prostate cancer as risk factors, while many putative risk factors, including androgens, diet, physical activity, sexual factors, inflammation, and obesity have been implicated, but their roles in prostate cancer etiology remain unclear. A significant impediment to developing effective preventive approaches against prostate cancer is the lack of a clear understanding as to the mechanisms by which these risk factors influence disease development and progression. The mechanisms by which aging impacts tumorigenesis are especially understudied, due to the complexities and co-morbidities associated with the aging process. This is especially true in the case of understanding how an aging immune system modulates prostate cancer initiation and progression. Relevant models in which specific components of the aging immune system can be recapitulated are critical for delineating the relationship between aging and tumorigenesis and studying the specific mechanisms by which aging modulates the disease process. Based upon the current understanding of the role of pro-inflammatory pathways in promoting tumorigenesis and our preliminary data demonstrating an induction of these pathways in prostate cancer cells in response to sera from a model of an aging immune system, we hypothesize that the altered immune function in the aging T lymphocyte may not merely be a passive, permissive event in tumor development, but may actively contribute to and promote prostate cancer initiation and progression through changes induced in the prostate cancer microenvironment. We propose to develop a highly unique and novel transgenic animal model to investigate how an aging immune system promotes prostate cancer initiation and progression. We will then assess how the changes in T cell function associated with aging modulate prostate cancer development. This model will be an invaluable tool for developing effective approaches for prevention and treatment of this pervasive disease, and will provide significant insight into the etiology and progression of the second leading cause of cancer deaths in men in the US.

? DESCRIPTION (provided by applicant): Over the last decade, a large body of evidence has established that obesity is associated with a worse breast cancer prognosis for both pre- and postmenopausal women. There are several mechanism(s) which have been proposed for promoting this effect, with recent evidence suggesting that the obese state is associated with changes in the biology of the disease, promoting a more aggressive phenotype. Clinically, obesity correlates with worse outcome on hormone therapy agents, most notably aromatase inhibitors (AI). Our group, as well as others, has demonstrated that obesity promotes increased local aromatase expression in the mammary gland. Our preliminary studies suggest that this induction is mediated primarily through cyclooxygenase (Cox)-derived prostaglandin E2 (PGE2), that this induction is associated with increased estrogen receptor ? (ER?) activity in mammary epithelial cancer cells, and most importantly, that regular use of NSAIDs may reduce the rate of recurrence on AIs by half. These data suggest that interventions that suppress COX-2 PGE2 production may provide significant benefit for the obese ER+ patient. Omega-3 fatty acids have demonstrated anti-cancer benefit through multiple mechanisms, including suppression of inflammation-related signaling. The omega-3 PUFAs serve as competitive substrates for COX- 2 activity, resulting in suppressed PGE2 production. Importantly, our preliminary data suggest that at physiological relevant levels DHA is able to inhibit obesity-induced PGE2 production in vitro. Our exceptional collaborative team of investigators will use highly integrated pre-clinical and clinical studies to test the novel hypothesis that omega-3 fatty acid supplementation can be used to improve response to AIs in the obese postmenopausal breast cancer patient population and prevent many of the tumor-promoting effects of obesity. The results of this study could have an immediate impact on patient outcomes by transitioning directly into a larger intervention trial evaluating both the proposed mechanism of resistance and the use of omega-3 fatty acid supplements to improve response.