Projects per year
Project Details
Description
OVERALL – APOBEC MUTAGENESIS IN BREAST CANCER
ABSTRACT
APOBEC signature mutations make up 20% of base-substitution mutations in primary tumors, which
increases to over 50% in metastases. Additional enrichment is often observed in estrogen receptor (ER)-
positive disease. APOBEC-catalyzed C-to-U lesions in single-stranded (ss)DNA lead to signature C-to-T and
C-to-G mutations within 5′-TCA and 5′-TCT trinucleotide motifs. In addition, APOBEC-derived C-to-U lesions
can be (mis)processed by cellular DNA repair enzymes, resulting in single- and double-stranded DNA breaks
and more complex chromosomal rearrangements. APOBEC expression levels and mutagenesis correspond
with poor clinical outcomes, such as shorter disease-free and overall survival in women with operable ER-
positive breast cancer. Elevated APOBEC levels also predict poor overall survival for patients diagnosed with
recurrent ER-positive metastases. These and other published data demonstrate that APOBEC mutagenesis is
ongoing in breast tumor cells and underpin our overarching Program hypothesis that inhibiting APOBEC will
prevent a large proportion of additional mutations from happening in residual ER-positive disease and will
thereby improve the durability of current treatments and result in better overall therapeutic outcomes. Three
multidisciplinary Projects will work together in an integrated and comprehensive manner to test this idea.
Project 1 will develop reporter systems for quantifying APOBEC activity in living cells and determine the
molecular mechanisms responsible for APOBEC regulation and for genomic uracil processing in breast cancer
cells. Project 2 will use chemical biology approaches to investigate the mechanism of APOBEC-catalyzed
ssDNA deamination and will develop nucleic acid and small molecule probes to inhibit APOBEC activity.
Project 3 will leverage structural and biophysical approaches to investigate global mechanisms for APOBEC
binding to ssDNA as well as the local structural features important for target sequence preferences and
inhibition of APOBEC enzymes in breast cancer. These Projects will be supported by service Cores for
administration, murine models, computational chemistry and biophysics, and enzymes and antibodies. Our
Program is poised to have both immediate and long-term impact for ER-positive breast cancer: immediate
impact by producing novel technologies and a comprehensive understanding of the mechanism of APOBEC
mutagenesis, and long-term impact on clinical translation through the development of technologies for
diagnosing APOBEC-positive disease and the creation of novel chemical matter to inhibit this mutational
process for therapeutic benefit.
Status | Active |
---|---|
Effective start/end date | 8/9/19 → 7/31/24 |
Funding
- National Cancer Institute: $95,930.00
- National Cancer Institute: $1,723,288.00
- National Cancer Institute: $80,536.00
- National Cancer Institute: $1,751,218.00
- National Cancer Institute: $1,683,415.00
- National Cancer Institute: $1,713,487.00
- National Cancer Institute: $1,656,507.00
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