Fas/FasL System In Normal Mammary Gland Development

说明：（由申请人提供）本提案响应了 RFA PA 99-162“乳房发育阶段：正常 转移性疾病“我们建议研究乳腺癌发生的机制， 发育和退化调节乳腺癌的发展。是我们 乳腺上皮细胞的程序性细胞死亡（PCD） 在退化过程中是由FasIFasL系统介导的。其他人和我们有 提出，与乳房退化相关的细胞凋亡赋予了对乳腺癌的抵抗力， 肿瘤发生，而不适当的生存的分泌上皮细胞 明显增加了肿瘤发展的易感性。因此，委员会认为， 限制增殖或导致乳腺上皮细胞死亡的条件可能 降低人类患乳腺癌的风险。我们的数据表明 乳腺细胞表面Fas受体蛋白的表达 在哺乳期结束时引发细胞凋亡。因此，Fas/FasL的改变， 系统可以调节具有潜在的增殖细胞的存活， 恶性转化我们的第二个假设是 可能是由于FasIFasL凋亡途径的失败， 通常消除老化或转化细胞，这些细胞有恶性肿瘤的风险。 转型Fas介导的凋亡信号的缺失导致了 在其表面上仅表达FasL的转化细胞的持续存在。到 为了证明我们假设的正确性，我们提出了一个四年计划：1）研究 Fas和FasL在正常小鼠乳腺中的表达及其在乳腺癌中的作用 腺体发育和重塑。2)Fas和FasL在正常人肝组织中的作用 以及Fas和FasL缺陷小鼠的病理性小鼠乳腺发育。 3)探讨Fas和FasL表达和功能的调控; 4)雌激素和选择性雌激素对FasL表达的调节 受体调节剂（SERMs）。 一条细线将正常发展与肿瘤发展区分开来。微妙的平衡 细胞生长和细胞凋亡之间的平衡维持这种稳态。一旦 这条线被打破了，保护生物体免受癌症侵害的相同基因可能 参与了它的起源。编码Fas和FasL的基因，通常 调节体内平衡但有可能促进恶性生长， 打破这种脆弱的平衡。对功能的更深入理解 以及参与组织稳态和肿瘤的基因的调节 抑制将提供与生物学相关的宝贵信息， 正常乳腺的发育。随着基础的改善， 正常的乳腺生理学，我们可以提高对乳腺癌的认识， 从而能够制定有效的治疗策略， 预防

DESCRIPTION: (Provided by the applicant) 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.