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Description
PROJECT 1 - BIOLOGY OF DNA DEAMINASES IN BREAST CANCER
ABSTRACT
Estrogen receptor (ER)-positive breast cancer is the most common form of breast cancer, accounting for
over 75% of invasive breast cancers diagnosed each year. The overall mutation landscape in ER-positive
breast cancer is multifactorial, but the DNA deaminase APOBEC3B (A3B) accounts for nearly 20% of base-substitution
mutations in primary disease and over 50% in metastases. A3B is not expressed in normal
mammary epithelial cells and becomes overexpressed in the majority of breast cancers. A3B overexpression
correlates with poor clinical outcomes for ER-positive breast cancer, including recurrence, metastasis, and
drug resistance. Our Program is testing the overarching hypothesis that A3B inhibition, as an adjuvant to
primary treatment options, will help to prevent detrimental mutation-driven outcomes such as drug resistance
and metastasis. Project 1 will contribute directly to collaborative Program efforts to test this hypothesis through
3 specific aims. In Aim 1, we propose to develop reporter systems for quantifying A3B-mediated editing in
living cells, including an innovative, transportable reporter. In one potential application, this system will enable
rapid testing of candidate small molecule A3B inhibitors in a panel of breast cancer cell lines as candidate
compounds are developed through the concerted activities of all Program components. In Aim 2, we will
delineate mechanisms of protein-level A3B regulation in normal and breast cancer cells. These studies will
focus on protein-protein interactions prioritized by proteomics data sets. Comprehensive characterization of
direct interactions is also anticipated to reveal potentially druggable surfaces for collaborative studies on
chemical probes (Project 2), computational modeling (Core C), and structural biology (Project 3). In Aim 3, we
will address how A3B-catalyzed genomic uracil lesions are processed into error-free and mutagenic outcomes
by different DNA repair pathways. These studies have the potential to reveal molecular dependencies in DNA
repair that are specific to breast tumor cells undergoing elevated levels of DNA damage catalyzed by A3B.
Thus, Project 1 is an integral component of this overall Program because it will provide innovative assays for
quantifying A3B activity in living breast cancer cells, yield molecular insights into regulatory and potentially
druggable protein surfaces, and uncover genetic dependencies that may constitute new opportunities for
diagnostic and therapeutic development.
Status | Active |
---|---|
Effective start/end date | 7/1/19 → 7/31/24 |
Funding
- National Cancer Institute: $270,112.00
- National Cancer Institute: $275,130.00
- National Cancer Institute: $80,536.00
- National Cancer Institute: $347,814.00
- National Cancer Institute: $348,174.00
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Projects
- 1 Active
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APOBEC MUTAGENESIS IN BREAST CANCER
Aihara, H., Amaro, R. E., Carpenter, M. A., Harki, D. A., Harris, R., Li, M., Yee, D., Harris, R. R. S., Harki, D. D. A., Yee, D. D., Aihara, H. & Amaro, R. R. E.
8/9/19 → 7/31/24
Project: Research project