CECR2 Drives Breast Cancer Metastasis by Suppressing Macrophage Inflammatory Responses

Abstract

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.

The emerging role of ISWI chromatin remodeling complexes in cancer

“…CECR2 has been found to be involved in the regulation of tumor immunity via macrophages. In this respect, upregulation of CECR2 in metastatic breast cancer is positively related to M2 macrophages and increases tumor metastasis by promoting M2 macrophage polarization to create an immunosuppressive microenvironment [ 139 ]. Mechanistically, CECR2 formed a complex with p65 through its bromodomain to activate the expression of the NF-κB target genes CSF1 and CXCL1 , which are critical for macrophage-mediated immune suppression at metastatic sites [ 139 ].…”

“…In this respect, upregulation of CECR2 in metastatic breast cancer is positively related to M2 macrophages and increases tumor metastasis by promoting M2 macrophage polarization to create an immunosuppressive microenvironment [ 139 ]. Mechanistically, CECR2 formed a complex with p65 through its bromodomain to activate the expression of the NF-κB target genes CSF1 and CXCL1 , which are critical for macrophage-mediated immune suppression at metastatic sites [ 139 ]. Correspondingly, the inhibition of CECR2 by targeting bromodomain arrests immunosuppression by macrophages and inhibits breast cancer metastasis [ 139 ].…”

“…Mechanistically, CECR2 formed a complex with p65 through its bromodomain to activate the expression of the NF-κB target genes CSF1 and CXCL1 , which are critical for macrophage-mediated immune suppression at metastatic sites [ 139 ]. Correspondingly, the inhibition of CECR2 by targeting bromodomain arrests immunosuppression by macrophages and inhibits breast cancer metastasis [ 139 ].…”