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Description
CORE B – MURINE MODELS
ABSTRACT
Accumulated mutations are often responsible for malignant phenotypes and the development of therapy
resistance in estrogen receptor (ER)-positive breast cancer. We have shown that the APOBEC family of DNA
cytosine deaminases is an important source of mutation in breast cancer and particularly in ER-positive
disease. One family member, APOBEC3B (A3B), is overexpressed and associated with aggressive
phenotypes, manifesting as early disease recurrence and decreased clinical benefit from tamoxifen. We have
corroborated these clinical data in a xenograft model in which A3B depletion increases and overexpression
decreases benefit from tamoxifen over time. Because mice lack an equivalent to the human A3B enzyme, and
because animal models will be vital for the long-term goal of providing more effective treatments for breast
tumors driven by the APOBEC mutational process, Core B will develop animal models for use by the Program
team, its collaborators, and the greater cancer research community. This goal will be achieved through 2
specific aims. Aim 1 will build on our published and preliminary results and advance the development of ER-
positive xenograft models for studies on resistance to estrogen deprivation (modeling aromatase inhibition),
cell cycle inhibition (CDK4/6 inhibition), and selective estrogen receptor degraders. Aim 2 will advance the
development of genetically engineered mouse models with a Cre-inducible A3B minigene by determining the
impact of mammary-specific expression of this enzyme in existing genetic backgrounds predisposed to
mammary tumors. The most robust A3B-driven models from Aims 1 and 2 will be used to test candidate A3B
inhibitors derived from pan-Program efforts led by Projects 2 & 3 and Cores C & D. We expect Core B models
to have a high impact by providing our Program team, its collaborators, and the greater cancer research
community with robust animal models to interrogate the APOBEC mutation process in vivo, which will be
essential for clinical translation and ultimately improving breast cancer survival rates.
Status | Finished |
---|---|
Effective start/end date | 7/1/19 → 7/31/23 |
Funding
- National Cancer Institute: $250,934.00
- National Cancer Institute: $316,312.00
- National Cancer Institute: $250,934.00
- National Cancer Institute: $250,934.00
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Projects
- 1 Active
-
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