BACKGROUND Claudin-low breast cancer is a molecular subtype associated with poor prognosis and without targeted treatment options. The claudin-low subtype is defined by certain biological characteristics, some of which may be clinically actionable, such as high immunogenicity. In mice, the medroxyprogesterone acetate (MPA) and 7,12-dimethylbenzanthracene (DMBA)-induced mammary tumor model yields a heterogeneous set of tumors, a subset of which display claudin-low features. Neither the genomic characteristics of MPA/DMBA-induced claudin-low tumors nor those of human claudin-low breast tumors have been thoroughly explored. METHODS The transcriptomic characteristics and subtypes of MPA/DMBA-induced mouse mammary tumors were determined using gene expression microarrays. Somatic mutations and copy number aberrations in MPA/DMBA-induced tumors were identified from whole exome sequencing data. A publicly available dataset was queried to explore the genomic characteristics of human claudin-low breast cancer and to validate findings in the murine tumors. RESULTS Half of MPA/DMBA-induced tumors showed a claudin-low-like subtype. All tumors carried mutations in known driver genes. While the specific genes carrying mutations varied between tumors, there was a consistent mutational signature with an overweight of T>A transversions in TG dinucleotides. Most tumors carried copy number aberrations with a potential oncogenic driver effect. Overall, several genomic events were observed recurrently; however, none accurately delineated claudin-low-like tumors. Human claudin-low breast cancers carried a distinct set of genomic characteristics, in particular a relatively low burden of mutations and copy number aberrations. The gene expression characteristics of claudin-low-like MPA/DMBA-induced tumors accurately reflected those of human claudin-low tumors, including epithelial-mesenchymal transition phenotype, high level of immune activation, and low degree of differentiation. There was an elevated expression of the immunosuppressive genes PTGS2 (encoding COX-2) and CD274 (encoding PD-L1) in human and murine claudin-low tumors. CONCLUSIONS Our findings show that the claudin-low breast cancer subtype is not demarcated by specific genomic aberrations, but carries potentially targetable characteristics warranting further research.

中文翻译：

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Claudin-low-like小鼠乳腺肿瘤显示出与基因组驱动程序无关的独特转录组模式。

背景技术克劳丁低度乳腺癌是与不良预后相关且没有靶向治疗选择的分子亚型。低claudin亚型由某些生物学特征定义，其中某些可能在临床上可操作，例如高免疫原性。在小鼠中，醋酸甲羟孕酮（MPA）和7,12-二甲基苯并蒽（DMBA）诱导的乳腺肿瘤模型产生一组异质性肿瘤，其中一部分表现出claudin低的特征。尚未深入探讨MPA / DMBA诱导的克劳丁低肿瘤的基因组特征和人克劳丁低乳腺肿瘤的基因组特征。方法利用基因表达芯片技术检测MPA / DMBA诱导的小鼠乳腺肿瘤的转录组学特征和亚型。从整个外显子组测序数据中鉴定出MPA / DMBA诱导的肿瘤中的体细胞突变和拷贝数异常。查询一个公开可用的数据集，以探索低克劳丁人乳腺癌的基因组特征，并验证鼠肿瘤中的发现。结果MPA / DMBA诱导的一半肿瘤表现为claudin-low-like亚型。所有的肿瘤都携带已知驱动基因的突变。尽管携带突变的特定基因在不同的肿瘤之间有所不同，但在TG二核苷酸中存在一致的突变特征，其中T> A转化超重。大多数肿瘤带有拷贝数异常，具有潜在的致癌驱动作用。总的来说，经常观察到一些基因组事件。然而，没有一个准确地描述克劳丁-低样肿瘤。人类克劳丁蛋白低的乳腺癌具有独特的基因组特征，尤其是相对较低的突变和拷贝数畸变负担。克劳丁低蛋白样MPA / DMBA诱导的肿瘤的基因表达特征准确反映了人类克劳丁低蛋白样肿瘤的基因表达特征，包括上皮-间质转化表型，高水平的免疫激活和低分化程度。在人和鼠类低claudin肿瘤中，免疫抑制基因PTGS2（编码COX-2）和CD274（编码PD-L1）表达升高。结论我们的研究结果表明，克劳丁低型乳腺癌亚型并未被特定的基因组畸变所界定，但具有潜在的可靶向特征，值得进一步研究。特别是突变和拷贝数畸变的负担相对较低。克劳丁低蛋白样MPA / DMBA诱导的肿瘤的基因表达特征准确反映了人类克劳丁低蛋白样肿瘤的基因表达特征，包括上皮-间质转化表型，高水平的免疫激活和低分化程度。在人和鼠类低claudin肿瘤中，免疫抑制基因PTGS2（编码COX-2）和CD274（编码PD-L1）表达升高。结论我们的研究结果表明，克劳丁低型乳腺癌亚型并未被特定的基因组畸变所界定，但具有潜在的可靶向特征，值得进一步研究。特别是突变和拷贝数畸变的负担相对较低。克劳丁低蛋白样MPA / DMBA诱导的肿瘤的基因表达特征准确反映了人类克劳丁低蛋白样肿瘤的基因表达特征，包括上皮-间质转化表型，高水平的免疫激活和低分化程度。在人和鼠类低claudin肿瘤中，免疫抑制基因PTGS2（编码COX-2）和CD274（编码PD-L1）表达升高。结论我们的研究结果表明，克劳丁低型乳腺癌亚型并未被特定的基因组畸变所界定，但具有潜在的可靶向特征，值得进一步研究。包括上皮-间质转化表型，高水平的免疫激活和低分化程度。在人和鼠类低claudin肿瘤中，免疫抑制基因PTGS2（编码COX-2）和CD274（编码PD-L1）表达升高。结论我们的研究结果表明，克劳丁低型乳腺癌亚型并未被特定的基因组畸变所界定，但具有潜在的可靶向特征，值得进一步研究。包括上皮-间质转化表型，高水平的免疫激活和低分化程度。在人和鼠类低claudin肿瘤中，免疫抑制基因PTGS2（编码COX-2）和CD274（编码PD-L1）表达升高。结论我们的研究结果表明，克劳丁低型乳腺癌亚型并未被特定的基因组畸变所界定，但具有潜在的可靶向特征，值得进一步研究。