Oncogenes and Luminal Apoptosis Within Mammary Acini

乳腺腺泡内的癌基因和管腔细胞凋亡

• 批准号: 6927888
• 负责人: Jayanta Debnath
• 金额: $ 4.48万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6927888
• 关键词: acinar cell; apoptosis; basement membrane; biological signal transduction; breast neoplasms; carcinogenesis; cell growth regulation; cell line; cell morphology; cellular polarity; cyclins; early diagnosis; epitope mapping; extracellular matrix; gene expression; genotype; laboratory mouse; mammary epithelium; neoplastic growth; oncogenes; phosphorylation; physiologic stressor; protein structure function; terminal nick end labeling; tissue /cell culture; western blottings

DESCRIPTION (provided by applicant): Glandular epithelial structures consist of a hollow lumen surrounded by polarized epithelial cells. Filling of this lumen is a poorly understood hallmark of early oncogenesis. This research proposal hypothesizes that apoptosis is critical for maintaining luminal space when an oncogenic proliferative stress is placed on a mammary epithelial acinus and that oncogenes able to fill the lumen use anti-apoptotic or prosurvival signals in combination with enhanced proliferation to populate luminal space. In order to elucidate the effect of oncogenes on epithelial architecture, we are using a three-dimensional culture system in which mammary epithelial cells form growth-arrested polarized acini with a hollow lumen. Preliminary studies strongly suggest that apoptosis is critical for generating and maintaining luminal space in these structures, particularly when oncogenic proliferation occurs within the acinus. However, certain oncogenes, like activated ErbB2, allow cells to survive in the lumen. Interestingly, Bim, a proapoptotic BH3 protein and TRAIL, a TNF family ligand, have been identified as two candidate molecules that may influence luminal apoptosis. This proposal intends to understand the role and regulation of signaling pathways involved in luminal cell death and clarify the mechanisms that cancer genes utilize to populate the lumen. Specifically, the project aims to: 1) determine mechanisms that influence luminal survival upon uncontrolled proliferation within an acinus; 2) examine the role of Bim on luminal apoptosis in oncogenic acini and identify additional "BH3 only" proteins involved in luminal apoptosis; 3) determine the role of TRAIL signaling pathway components on the morphogenesis of normal and malignant epithelial acini; and 4) examine the role of death receptor mediated signaling pathways on mouse mammary gland development. The long-term goals are to better understand early oncogenesis and identify candidate molecules useful as early detection markers and therapeutic targets in breast cancer. Dr. Jayanta Debnath, the principal investigator, is an M. D. who has completed residency training in anatomic pathology, and wishes to develop a independent research career, focusing on the biology of early oncogenic events during carcinoma progression. The sponsor, Dr. Joan Brugge, is a recognized leader in the signal transduction pathways regulating growth and survival in cancer.

描述（由申请人提供）：腺上皮结构由四个被极化上皮细胞包围的空心管腔组成。 填充该管腔是早期造成生成的标志知之甚少。 这项研究提案假设，当将致癌性增殖应激放在乳腺上皮毒素上时，凋亡对于维持管腔空间至关重要，并且能够填充管腔的肿瘤基因使用抗凋亡或prosurvival信号，并结合了增强的增殖来填充流明空间。 为了阐明癌基因对上皮结构的影响，我们使用了三维培养系统，其中乳腺上皮细胞与空心管腔形成了生长降落的偏振acini。 初步研究强烈表明，凋亡对于在这些结构中产生和维持腔内空间至关重要，尤其是在毒素内发生致癌性增殖时。 但是，某些癌基因（例如活化的ERBB2）使细胞在管腔中生存。 有趣的是，BIM是TNF家族配体的一种促凋亡的BH3蛋白和TRAIL，已被确定为可能影响腔凋亡的两个候选分子。 该建议旨在了解涉及腔细胞死亡的信号通路的作用和调节，并阐明癌症基因用来填充管腔的机制。 具体而言，该项目的目的是：1）确定在毒素内不受控制的增殖时影响腔内生存的机制； 2）检查BIM对腔凋亡在致癌性acini中的作用，并鉴定出参与腔凋亡的其他“仅BH3”蛋白； 3）确定跟踪信号通路成分对正常和恶性上皮肌的形态发生的作用； 4）检查死亡受体介导的信号通路对小鼠乳腺发育的作用。 长期目标是更好地理解早期发生的早期发生，并确定候选分子作为早期检测标记和乳腺癌的治疗靶标有用。 首席研究员Jayanta Debnath博士是M. D.，他已经完成了解剖病理学的居住培训，并希望发展独立的研究职业，重点是癌症过程中早期致癌事件的生物学。 赞助商琼·布鲁格（Joan Brugge）博士是信号转导途径的公认领导者，该途径调节癌症的生长和存活率。