Canine Mammary Carcinomas: A Comparative Analysis of Altered Gene Expression

Abstract

Breast cancer represents the second most frequent neoplasm in humans and sexually intact female dogs after lung and skin cancers, respectively. Many similar features in human and dog cancers including, spontaneous development, clinical presentation, tumor heterogeneity, disease progression and response to conventional therapies have supported development of this comparative model as an alternative to mice. The highly conserved similarities between canine and human genomes are also key to this comparative analysis, especially when compared to the murine genome. Studies with canine mammary tumor (CMT) models have shown a strong genetic correlation with their human counterparts, particularly in terms of altered expression profiles of cell cycle regulatory genes, tumor suppressor and oncogenes and also a large group of non-coding RNAs or microRNAs (miRNAs). Because CMTs are considered predictive intermediate models for human breast cancer, similarities in genetic alterations and cancer predisposition between humans and dogs have raised further interest. Many cancer-associated genetic defects critical to mammary tumor development and oncogenic determinants of metastasis have been reported and appear to be similar in both species. Comparative analysis of deregulated gene sets or cancer signaling pathways has shown that a significant proportion of orthologous genes are comparably up- or down-regulated in both human and dog breast tumors. Particularly, a group of cell cycle regulators called cyclin-dependent kinase inhibitors (CKIs) acting as potent tumor suppressors are frequently defective in CMTs. Interestingly, comparative analysis of coding sequences has also shown that these genes are highly conserved in mammals in terms of their evolutionary divergence from a common ancestor. Moreover, co-deletion and/or homozygous loss of the INK4A/ARF/INK4B (CDKN2A/B) locus, encoding three members of the CKI tumor suppressor gene families (p16/INK4A, p14ARF and p15/INK4B), in many human and dog cancers including mammary carcinomas, suggested their important conserved genetic order and localization in orthologous chromosomal regions. miRNAs, as powerful post-transcriptional regulators of most of the cancer-associated genes, have not been well evaluated to date in animal cancer models. Comprehensive expression profiles of miRNAs in CMTs have revealed their altered regulation showing a strong correlation with those found in human breast cancers. These genetic correlations between human and dog mammary cancers will greatly advance our understanding of regulatory mechanisms involving many critical cancer-associated genes that promote neoplasia and contribute to the promising development of future therapeutics.

Molecular Mechanisms of Canine Cancers

“…A comprehensive study done on expression levels of important cellular pathways in canine breast cancer found that cyclin-dependent kinase inhibitors, which regulate the cell cycle, are often dysfunctional. As expected, oncogenic pathways, such as PI3K/AKT, KRAS, MAPK, Wnt, βcatenin, BRCA2, ESR1 and P-cadherin, are upregulated while tumor suppressor pathways, like p53, p16/INK4A (encoded by CDKN2A), PTEN and E-cadherin, are downregulated ( Table 6) [71]. Mutations in any of the genes or proteins involved in these pathways can lead to failure to check important cell events before continuing the cell cycle, which can lead to tumorigenesis.…”

In vitro study to assess the efficacy of CDK4/6 inhibitor Palbociclib (PD‐0332991) for treating canine mammary tumours

“…CMTs share many similarities in molecular and clinical features with hBCa . Findings from different studies also suggest that CDK4/6 activity is aberrant in canine mammary tumour (CMT) cells.…”

The role of cyclin‐dependent kinases in oral potentially malignant disorders and oral squamous cell carcinoma

“…CDKs are a family of protein kinases with multiple functions, one of which is to regulate the cell cycle (Figure ) . Specifically, they act as checkpoints and drivers for the smooth transition from one phase to the next.…”