Background Despite recent progress in liquid biopsy technologies, early blood-based detection of breast cancer is still a challenge. Methods We analyzed secretion of the protein cellular communication network factor 1 (CCN1, formerly cysteine-rich angiogenic inducer 61) in breast cancer cell lines by an enzyme-linked immunosorbent assay (ELISA). Soluble CCN1 in the plasma (2.5 µL) of 544 patients with breast cancer and 427 healthy controls was analyzed by ELISA. The breast cancer samples were acquired at the time of primary diagnosis prior to neoadjuvant therapy or surgery. A classifier was established on a training cohort of patients with breast cancer and age-adapted healthy controls and further validated on an independent cohort comprising breast cancer patients and healthy controls. Samples from patients with benign breast diseases were investigated as additional controls. Samples from patients with acute heart diseases (n = 127) were investigated as noncancer controls. The diagnostic accuracy was determined by receiver operating characteristic using the parameters area under the curve, sensitivity, and specificity. Results CCN1 was frequently secreted by breast cancer cell lines into the extracellular space. Subsequent analysis of clinical blood samples from patients with breast cancer and age-adjusted healthy controls revealed an overall specificity of 99.0% and sensitivity of 80.0% for cancer detection. Remarkably, 81.5% of small T1 cancers were already CCN1-positive, while CCN1 concentrations in patients with benign breast lesions were below the threshold for breast cancer detection. Conclusions Circulating CCN1 is a potentially novel blood biomarker for the detection of breast cancer at the earliest invasive stage.

中文翻译：

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循环细胞通信网络因子 1 蛋白作为早期检测乳腺癌的敏感液体活检标志物

背景 尽管液体活检技术最近取得了进展，但基于血液的早期乳腺癌检测仍然是一个挑战。方法 我们通过酶联免疫吸附试验 (ELISA) 分析了乳腺癌细胞系中蛋白质细胞通讯网络因子 1（CCN1，以前是富含半胱氨酸的血管生成诱导物 61）的分泌。通过 ELISA 分析了 544 名乳腺癌患者和 427 名健康对照者血浆 (2.5 µL) 中的可溶性 CCN1。乳腺癌样本是在新辅助治疗或手术之前的初步诊断时获得的。在乳腺癌患者和年龄适应的健康对照的训练队列上建立了分类器，并在包括乳腺癌患者和健康对照的独立队列上进一步验证。研究了良性乳腺疾病患者的样本作为额外的对照。将来自急性心脏病患者（n = 127）的样本作为非癌症对照进行研究。诊断准确性由受试者工作特征使用曲线下面积、敏感性和特异性等参数确定。结果CCN1经常被乳腺癌细胞系分泌到细胞外空间。随后对乳腺癌患者和经年龄调整的健康对照者的临床血液样本的分析显示，癌症检测的总体特异性为 99.0%，敏感性为 80.0%。值得注意的是，81.5% 的小 T1 癌症已经是 CCN1 阳性，而良性乳腺病变患者的 CCN1 浓度低于乳腺癌检测的阈值。