Oncogenes and Luminal Apoptosis Within Mammary Acini

描述（由申请人提供）：腺上皮结构由极化上皮细胞包围的中空管腔组成。这个管腔的充盈是早期肿瘤发生的一个鲜为人知的标志。本研究假设，当乳腺上皮腺泡受到致癌性增殖应激时，细胞凋亡对于维持管腔空间至关重要，并且能够填充管腔的癌基因使用抗凋亡或促生存信号，并结合增强的增殖来填充管腔空间。为了阐明癌基因对上皮结构的影响，我们使用了一个三维培养系统，在这个系统中，乳腺上皮细胞形成生长受阻的极化腺泡和一个中空的管腔。初步研究强烈表明，细胞凋亡对于这些结构中产生和维持腔隙至关重要，特别是当腺泡内发生致瘤性增殖时。然而，某些致癌基因，如活化的ErbB2，允许细胞在管腔中存活。有趣的是，Bim（一种促凋亡的BH3蛋白）和TRAIL（一种TNF家族配体）已被确定为可能影响管腔凋亡的两个候选分子。本研究旨在了解参与管腔细胞死亡的信号通路的作用和调控，并阐明肿瘤基因填充管腔的机制。

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.