Dormancy Signatures and Metastasis in Estrogen Receptor Positive and Negative Breast Cancer

Breast cancers can recur after removal of the primary tumor and treatment to eliminate remaining tumor cells. Recurrence may occur after long periods of time during which there are no clinical symptoms. Tumor cell dormancy may explain these prolonged periods of asymptomatic residual disease and treatment resistance. We generated a dormancy gene signature from published experimental models and applied it to both breast cancer cell line expression data as well as four published clinical studies of primary breast cancers. We found that estrogen receptor (ER) positive breast cell lines and primary tumors have significantly higher dormancy signature scores (Pin vivo growth of ER positive MCF7 cells. The patient data analysis suggests that disseminated ER positive tumor cells carrying a dormancy signature are more likely to undergo prolonged dormancy before resuming metastatic growth. Furthermore, genes identified with this approach might provide insight into the mechanisms of dormancy onset and maintenance as well as dormancy models using human breast cancer cell lines.

乳腺癌在原发肿瘤切除并辅以清除残留肿瘤细胞的治疗后仍可复发。此类复发可在长达数年的无症状阶段后出现。肿瘤细胞休眠现象可解释这类长期存在的无症状残留病灶以及治疗抵抗问题。我们从已发表的实验模型中构建了休眠基因特征，并将其应用于乳腺癌细胞系表达数据，以及四项已发表的原发性乳腺癌临床研究数据集。我们发现，雌激素受体（Estrogen Receptor, ER）阳性的乳腺癌细胞系与原发肿瘤均具有显著更高的休眠基因特征评分（对应ER阳性MCF7细胞的体内生长）。对患者数据的分析表明，携带休眠基因特征的播散性ER阳性肿瘤细胞，在恢复转移性生长前更易进入长期休眠状态。此外，通过本方法筛选得到的基因，可为阐明肿瘤休眠的启动与维持机制，以及基于人乳腺癌细胞系的休眠模型研究提供新的研究思路。