Triple negative breast cancer (TNBC) is the most aggressive breast cancer subtype with no targeted treatment available. Although we have made tremendous progress in regards to the genetic drivers of this disease, we have limited understanding of the epigenomic alterations that drive specific molecular subtypes of breast cancers. The epigenome consists of an array of chromatin modifications, which collectively form a dynamic chromatin state that impinges upon gene expression networks critical for maintaining cellular identity. Therefore, specific epigenomic alterations may act as drivers of different molecular phenotypes, however we have limited understanding of how specific chromatin patterns may be associated with specific molecular signatures such as basal-like breast cancer. Since epigenetic enzymes are targetable and epigenetic processes are reversible in nature, they could prove to be excellent targets for novel therapeutic strategies against specific molecular phenotypes. Our preliminary data suggests tumor suppressor activities for UBR7, a novel histone modifier, in triple negative breast cancer. We show that UBR7 acts as a E3 ubiquitin ligase for monoubiquitination of histone H2B at K120 residue and may transcriptionally regulate molecular signatures for invasive breast cancers. These data provide rationale for in depth characterization of tumor-suppressor function of UBR7 and identification of therapeutic vulnerabilities imparted by UBR7 loss. Our hypothesis is that UBR7 is a potent tumor suppressor in triple negative breast and promotes invasive behavior in triple- negative breast cancer partly by regulation of cadherin pathway. The objective of this proposal is to first perform in depth characterization of UBR7 tumor-suppressor activity using mouse models, elucidation of downstream cellular processes/pathways and identification of inhibitors/protein targets to inhibit in UBR7-low triple-negative breast cancers.
We aim to 1) characterize tumor-suppressor role of UBR7 and determine the genetic context in which UBR7 loss promotes triple-negative breast cancers; 2) determine if UBR7 loss promotes EMT and breast cancer metastasis by alteration of chromatin states and Cadherin genes; and 3) determine genetic and pharmaceutical vulnerabilities of UBR7-deficient triple negative breast cancers. Overall, our studies will provide significant advances in understanding role of epigenome in triple-negative breast cancer tumor progression and define molecular mechanisms underlying contribution of new histone modifier to cancer development.

Public Health Relevance

Triple-negative breast cancer is an aggressive form of breast cancer with limited treatment strategies. We propose to study in depth mechanism of action of tumor-suppressive role of UBR7, a novel H2B ubiquitin ligase, in triple-negative breast cancer as well as identify potential therapeutic vulnerabilities imparted by its loss. Our work is expected to provide critical insights into the role of a new histone modifier in triple negative breast cancer, which could provide biological insights into role of epigenome in this deadly disease.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Cancer Genetics Study Section (CG)
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Dey, Sumana Mukherjee
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University of Texas MD Anderson Cancer Center
Internal Medicine/Medicine
United States
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