FBX044 mediated BRCA1 degradation in sporadic breast cancers

  • Hu, Yanfen (PI)

Project: Research project

Project Details

Description

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.
StatusFinished
Effective start/end date3/1/142/28/16

Funding

  • National Institutes of Health: $160,643.00
  • National Institutes of Health: $193,160.00

ASJC

  • Medicine(all)

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