Canine as a Comparative and Translational Model for Human Mammary Tumor

Abstract

Despite the advances in research and treatment of human breast cancer, its incidence rate continues to increase by 0.5% per year, and the discovery of novel therapeutic strategies for specific subtypes of human breast cancer remains challenging. Traditional laboratory mouse models have contributed tremendously to human breast cancer research. However, mice do not develop tumors spontaneously; consequently, genetically engineered mouse models or patient-derived xenograft models are often relied upon for more sophisticated human breast cancer studies. Since human breast cancer develops spontaneously, there is a need for alternative, yet complementary, models that can better recapitulate the features of human breast cancer to better understand the molecular and clinical complexities of the disease in developing new therapeutic strategies. Canine mammary tumors are one such alternative model that share features with human breast cancer, including prevalence rate, subtype classification, treatment, and mutational profiles, all of which are described in this review.

Keywords: Canine Mammary Tumor; Canine Somatic and Germline Mutation Profiles; Canine-Patient Derived Xenograft; Comparative Oncology Model.

Figure 1. Predisposed and non-predisposed canine breeds with phenotypically different mammary gland carcinomas. Predisposed breed: (A) A 9-year-old, intact female Maltese dog with large, multilobulated, and well-vascularized solid mammary gland carcinoma involving the right fifth mammary gland. (B) Geriatric female boxer dog with extensive and advanced-stage inflammatory mammary carcinoma affecting the right and left caudal mammary glands. Photo courtesy of Drs. Louis-Philippe de Lorimier (Centre Veterinaire Rive-Sud) and Nick Dervisis (Virginia-Maryland College of Veterinary Medicine).

Figure 2. Multiple host and tumor variables contributing to the biologic behavior. A 10-year-old, spayed female Golden Retriever with (A) histologic grade II mammary gland carcinoma surgically removed by regional excision of the left mammary glands 4 and 5 with incomplete margins. (B) Rapidly growing locally recurrent disease (yellow arrowheads) and (C) regional lymph node metastases (red arrowheads; left inguinal [single arrowhead] and left medial iliac lymph nodes [double arrowheads]) identified on computed tomography scan. (D) Serosanguinous abdominal fluid cytologically consistent with a malignant effusive process suggesting distant mammary carcinoma metastases within the peritoneal cavity. Magnification (A) and (D) 200×. Histology courtesy of Dr. Jonathan Samuelson (University of Illinois at Urbana-Champaign).

Figure 3. Establishing a biorepository of canine PDX models in immunodeficient mice. Surgical specimens from canine patients were divided into small pieces and transplanted into immunodeficient mice (P0 group). When tumors are grown in P0 mice, the xenografts are used for genomic analysis (e.g., WES, RNA seq, and CNA analysis) and then maintained in cryo-banks for preservation. After expanding and cryopreserving the tumor xenografts in immunodeficient mice (P1), they can be used for in vivo drug responsiveness screening.

PDX = patient-derived xenograft; WES = whole exome sequencing; RNA seq = RNA sequencing; CNA = copy number alteration.