Expression of P-glycoprotein and Breast Cancer Resistance Protein in Canine Mammary Tumors and in a Chemoresistant Mast Cell Tumor

Multidrug resistance (MDR) consists in the ability of cancer cells to become resistant towards different drugs and is frequently mediated by ABC-transporters efflux pumps, such as P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP), which are also infamous for conferring cancer cell stemness and aggressiveness, thereby imparting a poor prognosis. MDR has been extensively studied in human oncology, but less is known in veterinary medicine. The aims of the past three years of investigation on canine mammary tumors have been to determine the distribution of P-gp and BCRP in the different cellular components of hyperplasia and neoplasia, to compare P-gp and BCRP expression in the histological stages and grades of canine mammary carcinomas (CMSs), to describe P-gp and BCRP expression in the stroma associated with neoplasia, and to examine P-gp and BCRP expression in two aggressive types of CMSs, namely canine inflammatory mammary cancer and histological grade 3 non-inflammatory carcinomas. P-gp and BCRP immunohistochemical expression was significantly higher in malignant vs benign epithelial cells and hyperplastic epithelium of the mammary gland, in aggressive histotypes (simple vs complex carcinomas; inflammatory carcinoma vs non-inflammatory carcinoma, only for P-gp), and in histological grade 2 and 3 carcinomas vs grade 1. Neoplasia-associated fibroblasts showed an increased expression in stage II and grade 2 and 3 carcinomas compared with stage I and grade 1. An increased expression of P-gp and BCRP was found in a canine relapsing and chemoresistant cutaneous mast cell tumor after chemotherapy with Vinblastine e Prednisolone. Chemoresistance in this case could be related to an increased efflux of the drugs mediated by these transmembrane pumps. Evaluation of P-gp and BCRP could help in the identification of aggressive, invasive and chemoresistant canine tumors, and the dog could provide a useful spontaneous model for chemoresistant human tumors.