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 normal-like/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 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.
Highlights
Naturally-occurring mammary tumors are the most frequently diagnosed cancer in bitches
Using the survival fraction of cells that were given a 2 Gy dose of radiation (SF2, a recognized experimental measure of radiosensitivity), a range of intrinsic radiosensitivities was found to be present in the parental cell lines, with the REM-134 cell line showing significantly greater radioresistance compared with the human cell lines
REM-134 RR and REM-134 RR cells that had not been exposed to radiation for 6 months (REM-134 rr) showed similar levels of radioresistance; this suggested that the changes involved in the acquisition of the RR phenotype are maintained over a long period of time (Figure 1C)
Summary
Naturally-occurring mammary tumors are the most frequently diagnosed cancer in bitches These neoplasms represent ∼50% of all canine tumors [1], of which 50% are malignant [2,3,4]. Due to similarities in clinical features, relative age of onset, risk factors and tumor biology, canine mammary tumors (CMT) represent an excellent comparative and translational model for human breast cancer (HBC) [5,6,7]. Cancer cells that possess intrinsic radioresistance, or develop acquired resistance during RT, can repopulate the tumor site after treatment. This can lead to treatment failures with the development of tumor recurrence and/or metastatic disease. In order to develop treatment strategies to overcome/target the clinical issue of radioresistance, we require a detailed understanding of the mechanisms underlying acquired radioresistance
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