Gray Mark, Turnbull Arran K, Meehan James, Martínez-Pérez Carlos, Kay Charlene, Pang Lisa Y, Argyle David J
The Royal (Dick) School of Veterinary Studies and Roslin Institute, University of Edinburgh, Edinburgh, United Kingdom.
Translational Oncology Research Group, Institute of Genetics and Molecular Medicine, Western General Hospital, University of Edinburgh, Edinburgh, United Kingdom.
Front Vet Sci. 2020 Jul 23;7:439. doi: 10.3389/fvets.2020.00439. eCollection 2020.
Research using 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.
使用犬乳腺癌细胞系和自然发生的犬乳腺肿瘤进行的研究，不仅是增进对兽医患者癌症理解的基础模型，也被视为人类乳腺癌的优秀转化模型。人类乳腺癌通常采用放射治疗；然而，肿瘤反应既取决于固有放射敏感性，也取决于产生放射抗性的细胞的肿瘤再增殖。比较犬类和人类关于放射抗性机制的研究，可能会带来使两个物种都受益的新型癌症治疗方法。在本研究中，我们建立了一种犬乳腺癌（REM - 134）放射抗性（RR）细胞系，并研究了与获得性放射抗性发展相关的细胞机制。我们将这个抗性模型与我们之前建立的人类乳腺癌放射抗性细胞系（MCF - 7 RR、ZR - 751 RR和MDA - MB - 231 RR）进行了比较分析，通过遗传、分子和细胞生物学方法来表征内在差异。RR细胞表现出增强的侵袭/迁移能力，有表型证据提示上皮 - 间质转化。在REM - 134 RR、MCF - 7 RR和ZR - 751 RR细胞系之间，除了WNT、PI3K和MAPK途径激活外，还发现上皮和间质基因表达模式存在相似性。在产生放射抗性后，转录组数据表明亲本MCF - 7和ZR - 751细胞系从腔面A型分类转变为基底/HER2过表达型（MCF - 7 RR）和正常样/HER2过表达型（ZR - 751 RR）。这些放射抗性亚型与REM - 134和REM - 134 RR细胞系相似，它们被分类为HER2过表达型。据我们所知，我们的研究首次建立了犬乳腺癌RR细胞系模型，并对犬类和人类癌细胞系获得性放射抗性机制进行了比较遗传和表型分析。我们证明，人类和犬类细胞系在获得性放射抗性发展过程中发生的细胞过程是相似的；因此，我们的结果表明犬类模型适用于研究人类和犬类放射抗性乳腺癌，并且人类医学中使用的治疗策略也可能适用于兽医患者。
