This proposal responds to the programmatic priorities of RFA PA 99-162 """"""""Stages of breast development: normal to metastatic disease."""""""" We propose to study the mechanism by which mammary development and involution regulate the development of breast cancer. It is our general hypothesis that programmed cell death (PCD) of mammary epithelial cells during involution is mediated by the FasIFasL system. Others and we have proposed that apoptosis associated with breast involution confers resistance to tumorigenesis while inappropriate survival of the secretory epithelial cells apparently increases susceptibility to tumor development. Accordingly, conditions that limit proliferation or cause breast epithelial cell death could result in reduction of risk for breast cancer in humans. Our data indicates that the expression of Fas receptor protein on the mammary cell surface triggers apoptosis at the end of lactation. Thus, alterations in the Fas/FasL system may regulate the survival of proliferating cells that have the potential for malignant transformation. It is our second hypothesis that breast cancer may arise from the failure of the FasIFasL apoptotic pathway that would normally eliminate aging or transformed cells that are at risk of malignant transformation. The absence of the Fasmediated-apoptotic signal results in the persistence of transformed cells expressing only FasL on their surface. To prove the validity of our hypothesis we propose a four-year plan to: 1) Study Fas and FasL expression in normal mouse mammary gland and its role in mammary gland development and remodeling. 2) Study the role of Fas and FasL in normal and pathologic mouse mammary gland development in Fas and FasL deficient mice. 3) To investigate the regulation of Fas and FasL expression and function; and 4) Study the regulation of FasL expression by estrogen and selective estrogen receptor modulators (SERMs). A thin line separates normal from neoplastic development. A delicate balance between cell growth and cell apoptosis maintains this homeostatic state. Once that line is breached the same genes protecting the organism from cancer may become involved in its genesis. The genes encoding Fas and FasL, which normally regulate homeostasis yet have the potential to foster malignant growth, exemplify' this tenuous balance. A more thorough understanding of the function and regulation of the genes involved in tissue homeostasis and tumor suppression will provide valuable information related to the biology and development of the normal mammary gland. With an improved foundation of the normal mammary physiology, we can advance the understanding of breast cancer, allowing the development of effective strategies for its treatment and prevention.
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