Abstract An important outcome from gene expression profiling studies of human cancers is the identification of a molecular taxonomy of breast cancer, and in particular, description of the basal-like breast cancer (BBC) subtype. BBC is an aggressive subtype with frequent and early relapse and poor survival. Unfortunately, the mechanisms underlying the poor prognosis associated with BBC are unclear. The over-arching goal of this project was to employ mouse strains generated through the Collaborative Cross (CC), a large panel of recombinant inbred mice strains which can be converted to ‘outbred strains’ with reproducible genomes through the generation of recombinant inbred intercrosses (RIX). Female C3(1)/SV40 T antigen transgenic mice (C3-TAgs; FVB background), a model determined by genomic analysis to reflect the BBC subtype, were bred to recombinant inbred CC males, creating a cohort of 500+ F1 experimental mice in 20 RIX lines to examine various phenotypic and genotypic changes. Mice were weighed weekly and were palpated twice weekly to determine tumor latency. Tumor-bearing mice were observed for tumor progression ([21 day tumor volume - initial volume/initial volume] x 100) and multiplicity (number of tumors at 21 days). Subsequent cohorts of selected RIX lines were treated with trametinib (MEK1/2 inhibitor), BKM120 (panPI3K inhibitor) or everolimus (mTOR inhibitor), and after three weeks of treatment, the percent change in tumor volume was used to assess the objective response rate of the therapies. The average tumor latency of all RIX mice was 22.8 weeks; however 4 RIX lines (1566, 2014, 5155 and 5156) had significantly longer latencies (average 34.1-44.5 wks), while 3 RIX lines (1515, 5066, and 3067) were observed to develop palpable tumors significantly earlier. Line 3067 also had significantly increased body mass relative to parental C3Tag mice. Two lines (559 and 3140) were noted to have increased tumor multiplicity. Efficacy trials showed all of the RIX lines (relative to parental C3TAgs), demonstrated increased resistance to each chemotherapeutic agent studied, with three exceptions: line 559 was sensitive to trametinib; line 1515 was sensitive to BKM120; and line 8005 was sensitive to everolimus. These findings suggest the introduction of germline variation (by breeding C3TAg mice with CC lines) modulates host characteristics as well as BBC development and therapeutic responses. Genetic and genomic analyses (including sequencing of candidate gene regions and microarray analyses) are underway to identify dominant genetic modifiers and associated molecular targets underlying the observed differential phenotypes. We conclude that these RIX strains represent useful model systems for identifying genetic modifiers and host characteristics that influence the development and/or chemotherapeutic response of BBC. Citation Format: David Darr, Norman Sharpless, Charles Perou, Fernando Pardo-Manuel de Villena, Darla Miller, Katharine Bendt, Stephen D. Hursting. Germline genetic variation modulates tumor latency and response to therapy in a mouse model of basal-like breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2285. doi:10.1158/1538-7445.AM2015-2285