Fas/FasL System In Normal Mammary Gland Development

描述：(由申请人提供)本建议书回应 RFA PA 99-162“乳房发育阶段：正常”的方案优先事项 到转移性疾病。我们建议研究乳腺 乳腺癌的发生和消退调节着乳腺癌的发展。这是我们的 乳腺上皮细胞程序性死亡(PCD)的一般假设 在退化过程中是由FasIFasL系统介导的。其他人和我们有 提出与乳房退缩相关的细胞凋亡可以抵抗 分泌上皮细胞不适当存活时的肿瘤发生 显然会增加对肿瘤发展的易感性。因此， 限制增殖或导致乳房上皮细胞死亡的条件可能 从而降低人类患乳腺癌的风险。我们的数据显示 乳腺细胞表面Fas受体蛋白的表达 在哺乳期结束时触发细胞凋亡。因此，Fas/FasL的变化 系统可能调节有潜力的增殖细胞的生存 用于恶变。这是我们的第二个假设，乳腺癌 可能是由于FasIFasL凋亡通路的失败而引起的 通常消除有恶性风险的老化或转化的细胞 转型。Fas介导的凋亡信号的缺失导致了 转化的细胞在其表面仅表达FasL。至 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中的作用 腺体发育和重塑。2)研究Fas和FasL在正常皮肤中的作用 以及Fas和FasL缺陷小鼠的病理乳腺发育。 3)探讨Fas、FasL的表达与功能调节； 4)研究雌激素和选择性雌激素对FasL表达的调节 受体调节剂(SERM)。 一条细线将正常发育和肿瘤发育分开。微妙的平衡 细胞生长和细胞凋亡之间的关系维持这种动态平衡状态。一次 这条线被破坏了，保护有机体免受癌症侵袭的基因可能 参与它的起源。编码Fas和FasL的基因，通常 调节动态平衡却有可能助长恶性生长， 例证就是这种微不足道的平衡。对功能有更透彻的了解 与组织动态平衡和肿瘤相关的基因调控 抑制将提供有价值的与生物学和 正常乳腺的发育。有了更好的基础 正常的乳腺生理，我们可以提高对乳腺癌的认识， 允许制定有效的治疗和治疗策略 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.