Dormancy signatures and metastasis in estrogen receptor positive and negative breast cancer.
Dormancy signatures and metastasis in estrogen receptor positive and negative breast cancer.
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DOI：
10.1371/journal.pone.0035569
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Segall JE
中科院分区：
文献类型：
--
作者：
Kim RS;Avivar-Valderas A;Estrada Y;Bragado P;Sosa MS;Aguirre-Ghiso JA;Segall JE
乳腺癌在切除原发肿瘤和治疗以消除残留的肿瘤细胞后可能复发。复发可能发生在长时间没有临床症状之后。肿瘤细胞的休眠可以解释这些长期的无症状残留疾病和治疗抵抗。我们从已发表的实验模型中生成了休眠基因签名，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。我们发现，雌激素受体（ER）阳性乳腺细胞系和原发性肿瘤具有显著高于ER-细胞系和肿瘤的休眠标记分数（P<0.0000001）。此外，在4项研究中对所有ER+肿瘤进行分层分析，结果显示，与肿瘤具有高休眠评分（HDS）的患者相比，肿瘤具有低休眠评分（LDS）的患者复发风险高2.1倍（p<0.000005）。这一趋势在所有四项单独研究中都得到了证实。两个休眠基因BHLHE 41和NR 2F 1的抑制导致ER阳性MCF 7细胞的体内生长增加。患者数据分析表明，携带休眠特征的播散性ER阳性肿瘤细胞在恢复转移性生长之前更可能经历延长的休眠。此外，用这种方法鉴定的基因可能提供对休眠开始和维持的机制以及使用人乳腺癌细胞系的休眠模型的深入了解。
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 (P<0.0000001) than ER- cell lines and tumors. In addition, a stratified analysis combining all ER+ tumors in four studies indicated 2.1 times higher hazard of recurrence among patients whose tumors had low dormancy scores (LDS) compared to those whose tumors had high dormancy scores (HDS) (p<0.000005). The trend was shown in all four individual studies. Suppression of two dormancy genes, BHLHE41 and NR2F1, resulted in increased in 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.
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