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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Clinical Investigator Award (CIA) (K08)
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Study Section
Subcommittee G - Education (NCI)
Program Officer
Myrick, Dorkina C
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Harvard University
Anatomy/Cell Biology
Schools of Medicine
United States
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Radoshevich, Lilliana; Debnath, Jayanta (2011) ATG12-ATG3 and mitochondria. Autophagy 7:109-11
Radoshevich, Lilliana; Murrow, Lyndsay; Chen, Nan et al. (2010) ATG12 conjugation to ATG3 regulates mitochondrial homeostasis and cell death. Cell 142:590-600
Debnath, Jayanta (2009) Detachment-induced autophagy in three-dimensional epithelial cell cultures. Methods Enzymol 452:423-39
Kim, Sean H J; Park, Sunwoo; Mostov, Keith et al. (2009) Computational investigation of epithelial cell dynamic phenotype in vitro. Theor Biol Med Model 6:8
Kim, Sean H J; Debnath, Jayanta; Mostov, Keith et al. (2009) A computational approach to resolve cell level contributions to early glandular epithelial cancer progression. BMC Syst Biol 3:122
Debnath, Jayanta (2008) Detachment-induced autophagy during anoikis and lumen formation in epithelial acini. Autophagy 4:351-3
Hebner, Christy; Weaver, Valerie M; Debnath, Jayanta (2008) Modeling morphogenesis and oncogenesis in three-dimensional breast epithelial cultures. Annu Rev Pathol 3:313-39
Fung, Christopher; Lock, Rebecca; Gao, Sizhen et al. (2008) Induction of autophagy during extracellular matrix detachment promotes cell survival. Mol Biol Cell 19:797-806
Lock, Rebecca; Debnath, Jayanta (2008) Extracellular matrix regulation of autophagy. Curr Opin Cell Biol 20:583-8
Debnath, Jayanta; Baehrecke, Eric H; Kroemer, Guido (2005) Does autophagy contribute to cell death? Autophagy 1:66-74

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