Metastasis is the major cause of cancer-related deaths due to the lack of effective therapies. Emerging evidence suggests that certain epigenetic and transcriptional regulators drive cancer metastasis and could be targeted for metastasis treatment. To identify epigenetic regulators of breast cancer metastasis, we profiled the transcriptomes of matched pairs of primary breast tumors and metastases from human patients. We found that distant metastases are more immune inert with increased M2 macrophages compared to their matched primary tumors. The acetyl-lysine reader, cat eye syndrome chromosome region candidate 2 (CECR2), was the top up-regulated epigenetic regulator in metastases associated with an increased abundance of M2 macrophages and worse metastasis-free survival. CECR2 was required for breast cancer metastasis in multiple mouse models, with more profound effect in the immunocompetent setting. Mechanistically, the nuclear factor κB (NF-κB) family member v-rel avian reticuloendotheliosis viral oncogene homolog A (RELA) recruits CECR2 to increase chromatin accessibility and activate the expression of their target genes. These target genes include multiple metastasis-promoting genes, such as TNC , MMP2 , and VEGFA , and cytokine genes CSF1 and CXCL1 , which are critical for immunosuppression at metastatic sites. Consistent with these results, pharmacological inhibition of CECR2 bromodomain impeded NF-κB–mediated immune suppression by macrophages and inhibited breast cancer metastasis. These results reveal that targeting CECR2 may be a strategy to treat metastatic breast cancer.

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ABBREVIATIONS: ARDS = acute respiratory distress syndrome; BLA = biologics license application; EMR = electronic medical record; IT = information technology; PR = pathogen reduction; SDP(s) = single-donor platelet(s); TA-GVHD = transfusionassociated graft-versus-host disease.

Epigenetic and transcriptional changes are critical for metastasis, the major cause of cancer-related deaths. Emerging evidence suggest that metastatic tumor cells escape immune surveillance more efficiently than tumor cells in the primary sites, but the epigenetic mechanisms controlling immune evasion during cancer metastasis are poorly understood. By analyzing transcriptomes of matched metastatic and primary tumor samples from breast cancer patients, we found that immune escape genes and 14 of 29 immune-oncology targets are downregulated in matched metastatic samples compared to primary tumors. CIBERSORTx analysis identified an increase of M2-like tumor promoting macrophages in the metastasis tumors comparing to primary tumors. Among the dysregulated epigenetic regulators, acetyl-lysine reader CECR2 is the top candidate regulator of this change as its mRNA levels correlated with the ratio of M2 macrophages. Consistently, higher CECR2 protein levels are more frequently observed in metastatic tumors, and high CECR2 mRNA levels were associated with poor distant-metastasis free survival of breast cancer patients. CECR2 specifically promotes breast cancer metastasis, with more profound effect in the immunocompetent setting. Mechanistically, NF-κB family member RELA recruits CECR2 to certain NF-κB target genes, including CSF1 and CXCL1. CSF1 secreted by tumor cells is critical for CECR2 to stimulate polarization of tumor-associated macrophages to create immunosuppressive microenvironment at the metastatic sites. Pharmacological inhibition of CECR2 bromodomain blocks the expression of key NF-κB target genes and inhibit tumor cell migration and invasion. These results nominate novel therapeutic targets for the treatment of metastatic breast cancer.

A possible association between WHS and hepatic malignancy may be an important consideration in the care and management of WHS patients.