Targeting heterochromatic RNAs in high risk breast cancer
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: Non-technical overview of the research topic and relevance to breast cancer: 
 
 The survival rate of breast cancer patients has dramatically improved over the last two decades due to advances in diagnostics and therapeutics. However, a subpopulation where these advances are lacking are those individuals with a high risk for breast cancer due to genetic predisposition, such as mutations in BRCA1. Although identification of BRCA1 has led to a diagnostic tool for detection of mutations in the gene, BRCA1 mutated breast cancers remain highly aggressive and occur at young age of affected women. The evidence of a BRCA1 mutation has not yet allowed patients to be treated in more effective ways other than increased monitoring or radical measurement of prophylactic mastectomies. Therefore, understanding the mechanism of BRCA1 functioning as a tumor suppressor is critical in developing more effective treatments of familial breast cancer. New biomarkers that represent a functional loss of BRCA1 protein would promise early detection of the tumor onset thereby warranting more effective treatment. Furthermore, BRCA1 has also been shown to be mutated in sporadic breast cancers, and BRCA1-mutated breast cancer shares a number of pathological characters with a much larger group of hormone receptor negative breast cancers for which the targeted therapy is also lacking. Emerging evidence reveals that BRCA1 epigenetically controls the expression of noncoding RNAs, including oncogenic microRNAs and satellite RNA. We and others have shown that non-coding satellite RNAs are aberrantly overexpressed in BRCA1-mutant breast tumors and a number of other human epithelial malignancies. In this proposal, we are investigating the role of satellite RNA in causing breast tumor formation and determine what factors are required for the action of satellite RNA in tumorigenesis. 
 
 
 
 
 
 
 
 The question(s) or central hypotheses of the research: 
 
 Overexpression of heterochromatic satellite RNAs promotes tumorigenesis by binding and sequestering factors important for maintaining genomic integrity. 
 
 
 
 
 
 
 
 The general methodology: 
 
 To test our central hypothesis, we will establish two complementary mouse models to examine the tumorigenic potential of the heterochromatic satellite RNAs. We will use a proteomic approach to address why satellite RNA overexpression, which is one of the immediate consequences of loss of the BRCA1 function, will lead to genomic instability and tumor formation. 
 
 
 
 
 
 
 
 Innovative elements of the project and potential impact: 
 
 In this proposal, we use innovative animal models and a proteomic approach to determine novel ways by which disruption of the most silenced portion of the mammalian genome leads to cancer formation. The proposal is strongly supported by the preliminary data, the expected outcome will dramatically advance our understanding of non-coding RNAs expressed from the heterochromatin. It represents a new line of investigation in breast cancer research and has a potential to lead to a breakthrough in the field. The establishment of the satellite-RNA transgenic mouse models and validation and characterization of satellite RNA-binding proteins will improve our understanding of inherited and high risk breast cancer beyond an incremental advancement. The success of the proposal would have a significant clinical impact for patients with BRCA1 mutations by paving the way to develop satellite RNAs as a novel biomarker for early diagnosis. The acquired data will be critical for us to apply for more substantial funding to support large scale clinical investigations that move our research beyond cell lines and mouse models based tools.