Canine Mammary Tumors as a Potential Model for Human Breast Cancer in Comparative Oncology

Abstract

Clinical and molecular similarities between canine mammary tumors (CMTs) and human breast cancer (HBC) propel scientists to further study their application in comparative oncology as a model for human breast cancer. In total, 64 canine mammary tumors were selected to study the most common markers, which are applicable for human breast cancer treatment, including estrogen and progesterone receptors (ER and PR), human epidermal growth factor (HER2/neu), Ki67, and cyclooxygenase 2 (Cox2). Immunohistochemistry (IHC) was used to assess the protein expression. The Veterinary Nottingham Prognostic Index (Vet-NPI) was also computed. Moreover, univariate and multivariable Cox proportional hazard analyses were applied to estimate hazard ratios (HRs). The results demonstrated that Ki67 was strongly expressed in the triple-negative tumors, and Ki67 protein expression continuously increased over the increase of Cox2 protein expression (p < 0.001). Further analysis revealed a significant difference among canine mammary subtypes and Vet-NPI, in which triple-negative tumors displayed the highest mean score compared to other subtypes (p < 0.001). In addition, the multivariable analysis revealed that the regional mastectomy procedure (adjusted HR = 2.78 (1.14-6.8)), the triple-negative tumors (adjusted HR = 48.08 (7.74-298.8)), strong Ki67 protein expression group (adjusted HR = 7.88 (2.02-30.68)), and strong Cox2 protein expression group (adjusted HR = 29.35 (5.18-166.4)) demonstrated significantly lower disease-free survival rates compared to other corresponding groups. Overall, canine mammary tumors showed strong similarities to human breast cancer in terms of clinical and molecular aspects; therefore, they could be suggested as a model for human breast cancer in comparative oncology.

Figure 1

Representative images of CMT subtypes by IHC. ERα and PR protein expression was measured according to the percentage of cells with nuclear positivity. HER2 protein expression was quantified based on the percentage of cells with uniform intense complete membrane staining. The labeled images indicate subtypes of canine mammary tumors, including luminal A, luminal B triple-negative, and HER2-enriched. Scale bars are equal to 100 µm.

Figure 2

Representative images of Ki67 and Cox2 staining in canine mammary tumors by IHC. Ki67 protein expression was quantified based on the percentage of cells with positive nuclei. Cox2 protein expression was measured according to the proportion and intensity of cytoplasmic staining. Canine mammary adenocarcinomas with weak, moderate, and strong Ki67 staining as well as weak, moderate, and strong Cox2 staining. Scale bars are equal to 100 µm.

Figure 3

Pie charts of subtype frequencies comparing canine mammary tumors and human breast cancer. Pie charts show the frequency of subtypes in canine mammary tumors and human breast cancer that are nearly equal. (a) Frequency (%) of CMT subtypes in our study. (b) Frequency (%) of human breast cancer subtypes.

Figure 4

Tukey's post hoc test with 95% confidence interval. Tukey's post hoc test with a 95% confidence interval is conducted to evaluate the correlation between different subtypes with tumor size in centimeter (a), Ki67 in percentage (b), and Vet-NPI (c).

Figure 5

Kaplan–Meier plots indicating disease-free survival probabilities among 64 available canine mammary tumors. (a) Dogs having triple-negative (TN) tumors demonstrate significantly poor disease-free survival compared with other subtypes of canine mammary tumors (log-rank p < 0.001). (b, c) Tumors expressing high Ki67 and Cox2 protein displayed significantly poor disease-free survival compared with other tumor subgroups (log-rank p < 0.001). (d) Dogs presenting poor Vet-NPI indicated significantly poor disease-free survival compared with other groups (log-rank p < 0.001). For each Kaplan–Meier plot, a corresponding log-rank p value was presented.