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Abstract
About 20% of breast cancers in humans are basal-like, a subtype that is often triple negative and difficult to treat. An effective animal model for basal-like breast cancer (BLBC) is currently lacking and urgently needed. To determine if spontaneous mammary tumors in pet dogs could meet this need, we subtyped canine mammary tumors and evaluated the dog-human molecular homology at the subtype level. We applied various subtyping strategies to the RNA-seq data of 236 canine mammary tumors sequenced by others and us, and consistently identified two molecularly distinct subtypes. One subtype is mostly basal-like and clusters with human BLBC in PAM50 classification, while the other subtype does not cluster with any human breast cancer subtype. Furthermore, the canine basal-like subtype recaptures key molecular features (e.g., cell cycle gene upregulation) and gene expression patterns that characterize human BLBC. However, about 33% of canine basal-like tumors are estrogen receptor negative (ER-) and progesterone receptor positive (PR+), which is rare in human breast cancer. Further analysis reveals that these ER-PR+ canine tumors harbor additional basal-like features, including upregulation of genes of interferon-gamma response and of the Wnt-pluripotency pathway. Interestingly, we observed an association of PGR expression with gene silencing in all canine tumors, and with the expression of T cell exhaustion makers (e.g., PDCD1) in ER-PR+ canine tumors. In summary, we identify a canine mammary tumor subtype that molecularly resembles human BLBC overall, and thus could serve as a vital spontaneous animal model of this devastating breast cancer subtype.