Fas/FasL System In Normal Mammary Gland Development

正常乳腺发育中的 Fas/FasL 系统

• 批准号: 6365206
• 负责人: GIL G MOR
• 金额: $ 25.96万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-06-01 至 2004-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6365206
• 关键词: CD95 molecule; apoptosis; breast neoplasms; chemical carcinogenesis; cytokine; dimethylbenzanthracene; estrogen receptors; estrogens; estrus; gene induction /repression; gene targeting; genetically modified animals; genistein; hormone regulation /control mechanism; laboratory mouse; lactation; leukocytes; macrophage; mammary epithelium; mammary gland; methylnitrosourea; neoplasm /cancer immunology; pregnancy; raloxifene; tamoxifen

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.

描述：（由申请人提供）该提案回应了 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 发育和退化调节乳腺癌的发展。这是我们的 一般假设乳腺上皮细胞的程序性细胞死亡（PCD） 复旧期间由 FasIFasL 系统介导。别人和我们都有 提出与乳房复旧相关的细胞凋亡赋予对 肿瘤发生同时分泌上皮细胞的不适当存活 显然增加了肿瘤发展的易感性。因此， 限制增殖或导致乳腺上皮细胞死亡的条件可能 从而降低人类患乳腺癌的风险。我们的数据表明 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 的改变 系统可以调节具有潜力的增殖细胞的存活 用于恶变。我们的第二个假设是乳腺癌 可能是由于 FasIFasL 凋亡途径的失败引起的 通常会消除有恶性风险的老化或转化细胞 转变。 Fas 介导的细胞凋亡信号的缺失导致 转化细胞表面仅表达 FasL 的持久性。到 为了证明我们的假设的有效性，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对乳腺的作用 腺体发育和重塑。 2）研究Fas和FasL在正常情况下的作用 以及 Fas 和 FasL 缺陷小鼠的病理性小鼠乳腺发育。 3）研究Fas和FasL表达及功能的调控；和 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）。 一条细线将正常与肿瘤发展分开。微妙的平衡 细胞生长和细胞凋亡之间维持这种稳态。一次 该线路被破坏，与保护有机体免受癌症侵害的相同基因可能相同 参与其起源。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， 体现了这种脆弱的平衡。对函数的理解更加透彻 以及参与组织稳态和肿瘤的基因的调控 抑制将提供与生物学相关的有价值的信息 正常乳腺的发育。随着基础的不断完善 正常的乳腺生理机能，我们可以增进对乳腺癌的了解， 允许制定有效的治疗策略和 预防。