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 ∼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.

中文翻译：

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染色体1q21.3扩增是乳腺癌复发的可追踪生物标志物和可操作靶标。

肿瘤复发仍然是与乳腺癌相关的死亡率的主要原因，对于发现新的生物标记物和开发治疗方案以使处于高复发风险的乳腺癌患者受益的临床需求存在未满足的临床需求。在这里，我们报告鉴定在1q21.3处的染色体拷贝数扩增，该扩增富集了具有肿瘤起始细胞（TICs）特征的乳腺癌细胞亚群，并且与乳腺癌复发密切相关。不论乳腺癌亚型如何，扩增都存在于约10-30％的原发性肿瘤中，但超过70％的复发性肿瘤中。检测血液中无细胞DNA（cfDNA）的扩增与乳腺癌患者的早期复发密切相关，还可以用于追踪肿瘤对化学疗法的耐药性的出现。我们进一步显示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），以及与IL-1受体相关的激酶1（IRAK1）建立了相互的反馈回路驱动肿瘤球的生长。值得注意的是，该功能电路可能会被小分子激酶抑制剂pacritinib破坏，从而导致1q21.3扩增乳腺肿瘤的生长受到优先损害。我们的研究发现1q21.3定向的S100A7 / 8 / 9-IRAK1反馈回路是乳腺癌复发的重要组成部分，