Chromosome 1q21.3 amplification is a trackable biomarker and actionable target for breast cancer recurrence
Chromosome 1q21.3 amplification is a trackable biomarker and actionable target for breast cancer recurrence
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DOI：
10.1038/nm.4405
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发表时间：
2017-11-01
期刊：
影响因子：
82.9
通讯作者：
Yu, Qiang
中科院分区：
文献类型：
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作者：
Goh, Jian Yuan;Feng, Min;Yu, Qiang
肿瘤复发仍然是乳腺癌相关死亡的主要原因，对于发现新的生物标志物和开发治疗方案以造福乳腺癌高复发风险患者的临床需求尚未得到满足。在这里，我们报告了在1q21.3染色体拷贝数扩增的鉴定，该扩增在具有肿瘤起始细胞（tic）特征的乳腺癌细胞亚群中丰富，并且与乳腺癌复发密切相关。与乳腺癌亚型无关，10-30%的原发肿瘤中存在类似的扩增，但在70%以上的复发肿瘤中存在扩增。检测血液中游离DNA （cfDNA）的扩增与乳腺癌患者的早期复发密切相关，也可用于追踪肿瘤对化疗的耐药性的出现。我们进一步发现，1q21.3编码的S100钙结合蛋白（S100A）家族成员，主要是S100A7、S100A8和S100A9 (S100A7/8/9)，和IL-1受体相关激酶1 （IRAK1）建立了一个驱动肿瘤球生长的互反反馈回路。值得注意的是，这种功能电路可被小分子激酶抑制剂pacritinib破坏，导致1q21.3扩增乳腺肿瘤的生长优先受损。我们的研究发现，1q21.3导向的S100A7/8/9-IRAK1反馈回路是乳腺癌复发的重要组成部分，既是可追踪的生物标志物，也是可操作的乳腺癌治疗靶点。
Tumor recurrence remains the main reason for breast cancer-associated mortality, and there are unmet clinical demands for the discovery of new biomarkers and development of treatment solutions to benefit patients with breast cancer at high risk of recurrence. Here we report the identification of chromosomal copy-number amplification at 1q21.3 that is enriched in subpopulations of breast cancer cells bearing characteristics of tumor-initiating cells (TICs) and that strongly associates with breast cancer recurrence. Amplification is present in similar to 10-30% of primary tumors but in more than 70% of recurrent tumors, regardless of breast cancer subtype. Detection of amplification in cell-free DNA (cfDNA) from blood is strongly associated with early relapse in patients with breast cancer and could also be used to track the emergence of tumor resistance to chemotherapy. We further show that 1q21.3-encoded S100 calcium-binding protein (S100A) family members, mainly S100A7, S100A8, and S100A9 (S100A7/8/9), and IL-1 receptor-associated kinase 1 (IRAK1) establish a reciprocal feedback loop driving tumorsphere growth. Notably, this functional circuitry can be disrupted by the small-molecule kinase inhibitor pacritinib, leading to preferential impairment of the growth of 1q21.3-amplified breast tumors. Our study uncovers the 1q21.3-directed S100A7/8/9-IRAK1 feedback loop as a crucial component of breast cancer recurrence, serving as both a trackable biomarker and an actionable therapeutic target for breast cancer.