The prevalence of obesity, an established risk and prognostic factor for basal-like breast cancer (BLBC), has risen dramatically in the US and many other countries over the past 4 decades. Obesity is also associated with increased resistance to several classes of cancer chemotherapeutic agents used for advanced BLBC. Unfortunately the mechanisms underlying chemotherapy resistance, and the inter-individual differences driving resistance, are poorly understood. Population-based experimental mouse models for determining inter-individual genetic differences in chemotherapy pharmacokinetics and treatment-related efficacy or resistance in mammary gland cancer are not well-defined. Our aim is to develop a population-based experimental model based on outcrosses between 30 different Collaborative Cross line females and hemizygous male B6.FVB-Tg(C3-1-TAg) (greater than N15) congenic mice to produce 30 Collaborative Cross (CC) recombinant inbred line intercross (CC RIX) mouse lines to investigate the interactive effects between diet-induced obesity (DIO) and genetic susceptibility to chemotherapy in a genetically heterogeneous mouse model of BLBC. We report here that thirty genetically-different CCRIL X hemizygous B6.FVB-Tg(C3-1-TAg) congenic female and male CC RIX mice observed longitudinally for occurrence of basal-like mammary tumors showed significant differences in both age at first mammary tumor observation and the fraction of females and males in each RIX bearing tumors. Litter size and the number of females and males of each RIX varied across the 30 CC RIX line. The study was well-powered, with at least X males and Y females for each CC RIX line evaluated longitudinally. We observed that 25 of 30 female CC RIX lines presented with BLMC, with distinct times-to-tumor with each CC RIX. The penetrance of the fraction of each CC RIX line (birth cohort) presenting with BLMC varied greatly in females (25-100%). Surprisingly, 11 of 30 male CC RIX lines presented with BLMC, with penetrance of BLMC varying in males between 10-75%. In conclusion, we present preliminary data to support development of an experimental mouse model for BLBC based on the random mating of 8 genetically-diverse homozygous inbred founder lines followed by in-breeding to greater than 95% homozygosity carrying 45 million single-nucleotide and structural variants. Studies are underway using these CC RIX lines to evaluate the genetic underpinnings of obesity-associated resistance to carboplatin in C3-TAg-driven mammary tumors.

Citation Format: John Edgar French, William Pressel, Jody Albright, Melissa VerHague, Stephen D. Hursting. A population-based mouse model for an experimental basal-like mammary cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2256.