FBX044 mediated BRCA1 degradation in sporadic breast cancers

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ABSTRACT BRCA1 functions as a breast/ovarian tumor suppressor by promoting high fidelity DNA repair and maintaining genome stability. While germline mutations of BRCA1 account for approximately 50% of familial breast cancer cases, somatic mutations of the gene are rarely found in sporadic breast cancer. Rather, a large number of invasive sporadic breast tumors express wild-type BRCA1 protein at relatively low levels, raising the possibility that BRCA1 may also contribute to sporadic breast cancer development and progression. Given that sporadic breast cancers constitute approximately 90-95% of all breast cancer cases, understanding of the underlying mechanism by which BRCA1 expression is deregulated in sporadic cancer is highly significant and promises to have a broad impact on breast cancer etiology and treatment. Our preliminary work leads to the discovery of FBXO44, a key component of the SCFFBXO44 ubiquitin E3 ligase, that directly ubiquitinates BRCA1 and triggers its proteasome-mediated degradation in breast cancer cells. Importantly, FBXO44 is expressed at high levels in 90% of sporadic breast cancer with low BRCA1 expression. The objective of this application is to validate the hypothesis that aberrant expression of SCFFBXO44 results in reduced BRCA1 protein stability, which in turn leads to impaired DSB DNA repair and more aggressive tumor growth. To test this central hypothesis, we will examine the impact of FBXO44 on BRCA1 functions in DNA double-strand break repair, cell cycle checkpoint control, and tumor migration and invasion. In addition, we will seek to develop a pathway-specific tool to restore BRCA1 protein levels in sporadic cancer cells. When accomplished, the proposed work promises to elucidate a previously unappreciated mechanism of deregulated BRCA1 expression in sporadic cancer and inform development of novel therapeutic agents for sporadic breast cancer with low BRCA1 expression.