Comparative Analysis of the Development of Acquired Radioresistance in Canine and Human Mammary Cancer Cell Lines

Abstract

Research using in vitro canine mammary cancer cell lines and naturally-occurring canine mammary tumors are not only fundamental models used to advance the understanding of cancer in veterinary patients, but are also regarded as excellent translational models of human breast cancer. Human breast cancer is commonly treated with radiotherapy; however, tumor response depends on both innate radiosensitivity and on tumor repopulation by cells that develop radioresistance. Comparative canine and human studies investigating the mechanisms of radioresistance may lead to novel cancer treatments that benefit both species. In this study, we developed a canine mammary cancer (REM-134) radioresistant (RR) cell line and investigated the cellular mechanisms related to the development of acquired radioresistance. We performed a comparative analysis of this resistant model with our previously developed human breast cancer radioresistant cell lines (MCF-7 RR, ZR-751 RR, and MDA-MB-231 RR), characterizing inherent differences through genetic, molecular, and cell biology approaches. RR cells demonstrated enhanced invasion/migration capabilities, with phenotypic evidence suggestive of epithelial-to-mesenchymal transition. Similarities were identified between the REM-134 RR, MCF-7 RR, and ZR-751 RR cell lines in relation to the pattern of expression of both epithelial and mesenchymal genes, in addition to WNT, PI3K, and MAPK pathway activation. Following the development of radioresistance, transcriptomic data indicated that parental MCF-7 and ZR-751 cell lines changed from a luminal A classification to basal/HER2-overexpressing (MCF-7 RR) and normallike/HER2-overexpressing (ZR-751 RR). These radioresistant subtypes were similar to the REM-134 and REM-134 RR cell lines, which were classified as HER2-overexpressing. To our knowledge, our study is the first to generate a canine mammary cancer RR cell line model and provide a comparative genetic and phenotypic analysis of the mechanisms of acquired radioresistance between canine and human cancer cell lines. We demonstrate that the cellular processes that occur with the development of acquired radioresistance Gray et al. Canine Radioresistant Mammary Cancer Model are similar between the human and canine cell lines; our results therefore suggest that the canine model is appropriate to study both human and canine radioresistant mammary cancers, and that treatment strategies used in human medicine may also be applicable to veterinary patients.

REV1 Inhibition Enhances Radioresistance and Autophagy

“…Because cancer cell lines over the course of cancer treatment tend to acquire resistance to therapy, we tested whether REV1 inhibition may sensitize acquired radioresistant cell lines to radiation treatment. To test this hypothesis, we treated isogenic pairs of cancer cells, including human breast cancer cells (ZR751 and its radioresistant counterpart ZR-751 RR) and canine mammary cancer cells (REM and its radioresistant counterpart REM RR) [ 19 , 20 ], with increasing doses of drug 5 (7587885), JH-RE-06, and JH-RE-06.NaOH at 1 and 10 μM. Our results demonstrated no significant differences in cytotoxicity in the radioresistant cell lines compared to their isogenic parental controls ( Figure 2 C and Figure S5 ).…”

Establishment of a New Cell Line of Canine Mammary Tumor CMT-1026

“…CMT cells frequently show myoepithelial proliferation leading to preinvasive carcinoma (58,59). CMT-1026 is also a well-established basal like subtype cell line (60). Comparative pre-clinical studies of CMT-1026 and IPC-366 cell lines may be possible in the future.…”

Exosomes Derived from Radioresistant Breast Cancer Cells Promote Therapeutic Resistance in Naïve Recipient Cells

“…In general, there is a lack of radioresistant model systems to facilitate elucidating the mechanisms underlying the development of radioresistance. In our lab, we previously developed and extensively characterised novel in vitro radioresistant cell lines from human breast cancer (MCF-7, ZR-751 and MDA-MB-231) and canine mammary carcinoma (REM-134) cell lines [26,36]. We found that the radioresistance phenotype was maintained long term, even in the absence of radiation exposure, and concluded that the acquisition of radioresistance was not transient [26].…”