Programmed cell death (PCD) plays pivotal roles in tumor progression, cancer therapeutics and resistance of tumor cells to therapy. With the discovery that cancer cells often acquire mutations in key mechanisms that are involved in mediating PCD leading to the resistance to most anticancer therapies, non-apoptotic forms of programmed cell death have become attractive targets for novel approaches in anticancer therapy. Autophagy is an evolutionarily conserved cellular process responsible for self-cannabalization through a lysosomal degradation pathway. This leads to the degradation of long-lived proteins and'the turnover of various cytoplasmic organelles. Therefore, autophagy can be a highly efficient mode of cell death induction by excessive self-digestion. We hypothesize that an isoform ofthe C/EBPbeta transcription factor, C/EBPbeta-3 (or LIP), induces autophagy leading to massive cell death in human breast cancer cells. C/EBPbeta has been demonstrated to play an important role in mammary gland development and in breast cancers. We will test this hypothesis using the following specific aims:
Aim1 focuses on characterizing the induction of autophagy by LIP in breast cancer cell lines. Using qualitative and quantitative biochemical methods, we will determine if LIP induces autophagy.
Aim 2 focuses on characterizing changes in the transcriptome due to LIP expression in breast cancer cell lines. Gene expression profiling and miRNA arrays will be used to catalog changes in the transcriptome upon the expression of LIP.
Aim 3 focuses on the role of changes in the transcriptome in the induction of autophagy. For each of these molecules we will alter the expression by shRNA in order to determine their importance in the induction of autophagy. Relevance to public health: Among women in the U.S., breast cancer is still the most common cancer and the second most common cause of cancer death. One ofthe hallmarks of human cancers is the inherent or acquired resistance to apoptotic cell death. It has been established that defects in apoptosis may contribute to carcinogenesis, tumor progression, and treatment resistance. Most current anticancer therapies including chemotherapy, primarily act by activating the apoptotic cell death pathway in cancer cells. Therefore, a better understanding of the mechanisms controlling autophagy and identifying new agents capable of inducing extensive autophagy has vast potential to improve cancer therapeutics by enabling effective induction of an alternative death pathway, especially in, but not limited to, tumor cells that are resistant to apoptosis.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1-CB-N (29))
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Toliver, Adolphus
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Vanderbilt University Medical Center
Anatomy/Cell Biology
Schools of Medicine
United States
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