Abstract
The 1q21.3 amplification can be detected in cfDNA from most patients with recurrent breast cancer.
Major finding: The 1q21.3 amplification can be detected in cfDNA from most patients with recurrent breast cancer.
Mechanism: 1q21.3 harbors S100A7/8/9 which promote IRAK1 phosphorylation and cell growth.
Impact: 1q21.3 amplification may serve as a biomarker of recurrence and confer sensitivity to IRAK inhibitors.
In patients with breast cancer, biomarkers are needed to determine which patients are at high risk of recurrence. A better understanding of the molecular drivers of tumor recurrence may lead to the identification of biomarkers and development of targeted therapies. Using integrative genomic analyses Goh, Feng, Wang, and colleagues found that a 1q21.3 chromosomal amplification is enriched in tumor-initiating cells and associated with recurrent tumors in breast cancer. The 1q21.3 amplification was present in both ER+ and ER− tumors and, although the amplification was present in approximately 10% to 30% of primary tumors, it occurred in more than 70% of recurrent tumors. Droplet digital PCR was able to detect the 1q21.3 amplification in cfDNA from patient blood, with a sensitivity of 93.3% and a specificity of 97.5%, suggesting the feasibility of a liquid biopsy to identify patients with breast cancer with a high risk of recurrence. The 1q21.3 locus encodes members of the S100A calcium binding protein gene family, which act upstream of Toll-like receptor signaling to activate IRAK–NFκB. Accordingly, S100A7, S100A8, and S100A9 were upregulated in 1q21.3-amplified breast cancer cells, and their depletion reduced IRAK1 phosphorylation and cell growth in tumorspheres. Conversely, IRAK1 depletion downregulated S100A8/9, indicating a reciprocal regulation. In 18 of 25 sets of paired primary and recurrent breast tumors, IRAK1 phosphorylation and S100A8 expression were elevated in the recurrent samples. Further, 1q21.3 amplified cells were sensitive to the JAK2 inhibitor pacritinib, which has also been reported to inhibit IRAK1, both in vitro and in vivo. Moreover, in mice pacritinib was effective and well tolerated in combination with chemotherapy. Altogether, these findings suggest that 1q21.3 amplification may serve as a biomarker to identify patients with breast cancer at risk of recurrence and identify IRAK1 as a potential therapeutic target in these tumors, supporting further investigation of IRAK inhibitors, such as pacritinib, in breast cancer.
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