Department of Internal Medicine (DiMI), University of Genoa and Ospedale Policlinico San Martino, Viale Benedetto XV, 6, 16132, Genoa, Italy.
Comprehensive Cancer Center Leon Berard, Lyon, France.
Breast Cancer Res Treat. 2019 Sep;177(2):335-343. doi: 10.1007/s10549-019-05313-w. Epub 2019 Jun 20.
Breast cancer (BC) is a heterogeneous disorder, with variable response to systemic chemotherapy. Likewise, BC shows highly complex immune activation patterns, only in part reflecting classical histopathological subtyping. Schlafen-11 (SLFN11) is a nuclear protein we independently described as causal factor of sensitivity to DNA damaging agents (DDA) in cancer cell line models. SLFN11 has been reported as a predictive biomarker for DDA and PARP inhibitors in human neoplasms. SLFN11 has been implicated in several immune processes such as thymocyte maturation and antiviral response through the activation of interferon signaling pathway, suggesting its potential relevance as a link between immunity and cancer. In the present work, we investigated the transcriptional landscape of SLFN11, its potential prognostic value, and the clinico-pathological associations with its variability in BC.
We assessed SLFN11 determinants in a gene expression meta-set of 5061 breast cancer patients annotated with clinical data and multigene signatures.
We found that 537 transcripts are highly correlated with SLFN11, identifying "immune response", "lymphocyte activation", and "T cell activation" as top Gene Ontology processes. We established a strong association of SLFN11 with stromal signatures of basal-like phenotype and response to chemotherapy in estrogen receptor negative (ER-) BC. We identified a distinct subgroup of patients, characterized by high SLFN11 levels, ER- status, basal-like phenotype, immune activation, and younger age. Finally, we observed an independent positive predictive role for SLFN11 in BC.
Our findings are suggestive of a relevant role for SLFN11 in BC and its immune and molecular variability.
乳腺癌（BC）是一种异质性疾病，对全身化疗的反应各不相同。同样，BC 表现出高度复杂的免疫激活模式，这仅部分反映了经典的组织病理学亚型。我们独立描述的 Schlafen-11（SLFN11）是一种核蛋白，作为癌细胞系模型中对 DNA 损伤剂（DDA）敏感的因果因素。SLFN11 已被报道为人类肿瘤中 DDA 和 PARP 抑制剂的预测生物标志物。SLFN11 已被牵连到几个免疫过程中，如通过干扰素信号通路的激活来成熟胸腺细胞和抗病毒反应，这表明其作为免疫和癌症之间联系的潜在相关性。在本工作中，我们研究了 SLFN11 的转录图谱，其潜在的预后价值以及与 SLFN11 变异性的临床病理关联。
我们评估了 SLFN11 在 5061 名具有临床数据和多基因特征注释的乳腺癌患者的基因表达荟萃分析中的决定因素。
我们发现有 537 个转录物与 SLFN11 高度相关，确定“免疫反应”、“淋巴细胞激活”和“T 细胞激活”为顶级基因本体过程。我们确立了 SLFN11 与基底样表型的基质特征以及雌激素受体阴性（ER-）BC 对化疗的反应之间的强烈关联。我们鉴定了一个具有高 SLFN11 水平、ER-状态、基底样表型、免疫激活和年轻年龄的独特亚组患者。最后，我们观察到 SLFN11 在 BC 中具有独立的阳性预测作用。
我们的研究结果表明 SLFN11 在 BC 及其免疫和分子变异性中具有重要作用。
