SUMMARY:
The lack of understanding how genetic variants affect molecular mechanisms that mediate TNBC aggression
and impact effective anti-tumor therapies poses a substantial obstacle to advancement in cancer therapies.
Current genetically engineered mouse models (GEMMs) of TNBC lack genetic complexity because mice are
on a single inbred background which impairs the rigorous investigation into how individual genetic variation
might impact tumor initiation, progression, or response to therapy. Because of this limitation, pre-clinical
models typically fail to translate well to impact patient care. Although human studies have identified risk factors
for developing TNBC with both environmental and genetics approaches, studies often fall short due to the
inability to control variables or sample enough individuals. To address these limitations, we have pioneered a
transformative approach with the creation of a novel murine model with robust, reliable, and reproducible
phenotypic and genomic variation. We systematically crossed the C3(1)-Tantigen (C3Tag) GEMM, well
established to resemble human basal-like TNBC, into the BXD family - the largest and best characterized
genetic reference population. Preliminary data demonstrate that BXD-TNBC F1 isogenic hybrids have greatly
differing severity of TNBC phenotypes, indicating genetic modifiers that impact disease. The advantage of the
BXD-TNBC hybrids is that every genome is defined and reproducible. Using cutting edge systems genetics
and molecular candidate validation, we will identify genetic modifiers of TNBC. Cross-species comparisons
with publicly available human GWAS and genomic databases will identify conserved, biologically relevant, and
targetable candidates to yield highly impactful and readily translatable findings. We hypothesize that the
interaction of modifier and causal genes govern the heterogeneity of TNBC phenotypes and alter response to
therapy. Aim 1 will identify and validate novel genetic modifiers of TNBC phenotypes through unbiased
systematic quantification of TNBC severity and heritability across BXD-TNBC hybrids. Pilot studies revealed
candidate genes that impact patient survival in TNBC. Aim 2 will identify and validate novel genetic modifiers of
therapeutic efficacy across BXD-TNBC hybrids. Last, the genetic contribution linking obesity and TNBC is
currently unknown which is a problem because obesity exacerbates poor BC outcomes and reduces
therapeutic efficacy in patients. Aim 3 will identify genetic modifiers of susceptibility to obesity exacerbated
TNBC. Capitalizing upon our team’s expertise, the overall objective is to interrogate this replicable genetic
resource using established successful strategies to inform on the genetics of human risk and response to
therapy. In sum, the lack of targeted therapies for TNBC presents a great unmet clinical need. The deliverables
of this novel BXD-TNBC will define susceptibility loci, candidate genes, and molecular networks that underlie
variation of multiple TNBC phenotypes. Results generated will thus be transformative with high impact, leading
to the identification of genes modifying heterogeneity and networks underlying individual differences in TNBC.