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.
Depletion or inhibition of CECR2 impedes breast cancer metastasis by suppressing NF-κB signaling, migration, invasion, and immune suppression.
Breast cancer metastasis is thought to be driven through both epigenetic and transcriptional regulators, either of which could be targeted as a therapeutic strategy. Here, Zhang et al. identified the acetyl-lysine reader, CECR2, as an epigenetic regulator required for breast cancer metastasis in mouse models. CECR2 promoted M2 macrophage polarization and increased expression of metastasis-associated signaling molecules. Deletion or pharmacological inhibition of CECR2 prevented breast cancer metastasis in mouse models, suggesting that CECR2 should be explored as a therapeutic target for breast cancer.