Oncogenes and Luminal Apoptosis Within Mammary Acini

描述（由申请方提供）：腺上皮结构由极化上皮细胞包围的中空腔组成。 该腔的充盈是早期肿瘤发生的一个知之甚少的标志。 这项研究建议假设，细胞凋亡是至关重要的维持管腔空间时，致癌增殖压力被放置在乳腺上皮腺泡和癌基因能够填充管腔使用抗凋亡或促生存信号结合增强增殖填充管腔空间。 为了阐明癌基因对上皮结构的影响，我们使用三维培养系统，其中乳腺上皮细胞形成具有中空腔的生长停滞极化腺泡。 初步研究强烈表明，细胞凋亡是至关重要的产生和维持这些结构中的腔空间，特别是当致癌增殖发生在腺泡内。 然而，某些癌基因，如激活的ErbB 2，允许细胞在管腔中存活。 有趣的是，Bim，一种促凋亡的BH 3蛋白和TRAIL，一种TNF家族配体，已被鉴定为可能影响管腔凋亡的两种候选分子。 该提案旨在了解参与管腔细胞死亡的信号通路的作用和调节，并阐明癌症基因用于填充管腔的机制。 具体而言，该项目旨在：1）确定在腺泡内不受控制的增殖后影响管腔存活的机制; 2）检查Bim对致癌腺泡中管腔凋亡的作用，并鉴定参与管腔凋亡的另外的“仅BH 3”蛋白; 3）确定TRAIL信号通路组分对正常和恶性上皮腺泡的形态发生的作用;以及4）研究死亡受体介导的信号通路在小鼠乳腺发育中的作用。 长期目标是更好地了解早期肿瘤发生，并确定候选分子作为乳腺癌的早期检测标志物和治疗靶点。 博士首席研究员Jayanta Debnath是M。D.他已经完成了解剖病理学的住院医师培训，并希望发展一个独立的研究生涯，专注于癌症进展过程中早期致癌事件的生物学。 申办者Joan Brugge博士是调节癌症生长和存活的信号转导途径的公认领导者。

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.