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.
CORE B ? MURINE MODELS NARRATIVE APOBEC mutagenesis is a major contributor to the overall heterogeneity and subclonal diversity observed in breast cancer. This service core will develop murine models of mutagenesis by human APOBEC enzymes, which will be used by the Program and its collaborators for in vivo studies and provided to cancer researchers worldwide for complementary work with other tumor types. These models will enable preclinical testing of APOBEC activity modulators in vivo and, ultimately, will expedite clinical translation and improvements in breast cancer survival rates.
