Abstract 3708: Multiomic validation of canine simple carcinoma as a model for human basal-like breast cancer

Abstract

Abstract Roughly 20% of all breast cancer (BC) cases in humans are classified as basal-like breast cancer (BLBC), the deadliest subtype with a five-year survival prognosis lower than any other subtype. BLBC usually lacks the clinically targetable receptors estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). One of the main challenges in BLBC research is the lack of a spontaneous cancer model. To address this deficiency, we performed a comprehensive dog-human multiomic comparison. Briefly, we characterized the genomic and transcriptomic alterations of >100 spontaneous canine mammary cancer cases, including simple carcinoma (SC), a common subtype in pet dogs, from our own data and published studies by others. We then evaluated the dog-human molecular homology by comparing our canine findings to the studies of BLBCs from The Cancer Genome Atlas (TCGA). Our study shows a strong dog-human molecular homology. First, cross-species PAM50 classification indicates significant grouping of canine SC with human BLBC, but not other BC subtypes. This is supported by unsupervised clustering of a panel of recently published ~1800 cancer genes that characterize human BLBC. Second, gene set enrichment analysis with 44 BC molecular signatures, 20 of which are BLBC-specific, indicates that canine SCs have the same enrichment patterns as human BLBCs. Third, canine SCs show the same overall copy number alteration (CNA) patterns as human BLBCs. Specifically, canine SCs have significantly more amplified/deleted genes and a much greater percentage of the genome with CNA than other mammary cancer subtypes of the dog, which is also true for human BLBC. Furthermore, canine SC shares significantly more amplified/deleted genes with BLBC than any other BC subtypes. Importantly, these shared genes are strongly enriched in known BLBC signatures, including the 8q23-24 amplicon (containing the oncogene MYC) and chromosomal instability regulation. Finally, as with the PAM50 analysis, unsupervised cross-species clustering with amplified/deleted genomic regions and genes indicates a strong homology between canine SCs and human BLBCs. In conclusion, canine SC faithfully recapitulates the molecular features of human BLBC, and can effectively serve as a much-needed spontaneous cancer model for BLBC research. Canine SC will accelerate basic research, e.g., providing a novel dog-human comparison strategy for cancer driver-passenger discrimination. Canine SC will also accelerate the bench-to-bedside translation by bridging the gap between preclinical studies in mice and human clinical trials. Citation Format: Joshua L. Watson, Yuan Feng, Shaying Zhao. Multiomic validation of canine simple carcinoma as a model for human basal-like breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3708.