CECR2 drives breast cancer metastasis by promoting NF-κB signaling and macrophage-mediated immune suppression

Meiling Zhang, Zongzhi Z Liu, Keisuke Aoshima, Wesley L Cai, Hongyin Sun, Tianrui Xu, Yangyi Zhang, Yongyan An, Jocelyn F Chen, Lok Hei Chan, Asako Aoshima, Sabine M Lang, Zhenwei Tang, Xuanlin Che, Yao Li, Sara J Rutter, Veerle Bossuyt, Xiang Chen, Jon S Morrow, Lajos Pusztai, David L Rimm, Mingzhu Yin, Qin Yan

SCIENCE TRANSLATIONAL MEDICINE | 2 Feb 2022 | Vol 14, Issue 630

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.