(1) Zhang M (2) Liu ZZ (3) Aoshima K (4) Cai WL (5) Sun H (6) Xu T (7) Zhang Y (8) An Y (9) Chen JF (10) Chan LH (11) Aoshima A (12) Lang SM (13) Tang Z (14) Che X (15) Li Y (16) Rutter SJ (17) Bossuyt V (18) Chen X (19) Morrow JS (20) Pusztai L (21) Rimm DL (22) Yin M (23) Yan Q
Zhang et al. demonstrated that the acetyl-lysine reader, cat eye syndrome chromosome region candidate 2 (CECR2), is highly expressed in breast cancer metastases and correlates with increased M2 macrophage abundance. CECR2 interacts with acetylated RELA through its bromodomain to increase chromatin accessibility, and activates EMT genes and nuclear factor kappaB (NF-𝜅B) target genes, such as CSF1, CSF2, CXCL1, TNC, and VEGFA. Genetic and pharmacological inhibition of CECR2 suppressed NF-κB target gene expression, M2 macrophage polarization, and breast cancer metastasis in multiple mouse breast cancer models.
Contributed by Shishir Pant
(1) Zhang M (2) Liu ZZ (3) Aoshima K (4) Cai WL (5) Sun H (6) Xu T (7) Zhang Y (8) An Y (9) Chen JF (10) Chan LH (11) Aoshima A (12) Lang SM (13) Tang Z (14) Che X (15) Li Y (16) Rutter SJ (17) Bossuyt V (18) Chen X (19) Morrow JS (20) Pusztai L (21) Rimm DL (22) Yin M (23) Yan Q
Zhang et al. demonstrated that the acetyl-lysine reader, cat eye syndrome chromosome region candidate 2 (CECR2), is highly expressed in breast cancer metastases and correlates with increased M2 macrophage abundance. CECR2 interacts with acetylated RELA through its bromodomain to increase chromatin accessibility, and activates EMT genes and nuclear factor kappaB (NF-𝜅B) target genes, such as CSF1, CSF2, CXCL1, TNC, and VEGFA. Genetic and pharmacological inhibition of CECR2 suppressed NF-κB target gene expression, M2 macrophage polarization, and breast cancer metastasis in multiple mouse breast cancer models.
Contributed by Shishir Pant
ABSTRACT: 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.
Author Info: (1) Department of Pathology, Yale School of Medicine, New Haven, CT 06520, USA. (2) Laboratory of Comparative Pathology, Department of Veterinary Clinical Sciences, Faculty of Vete
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Author Info: (1) Department of Pathology, Yale School of Medicine, New Haven, CT 06520, USA. (2) Laboratory of Comparative Pathology, Department of Veterinary Clinical Sciences, Faculty of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan. (3) Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, PA 15232, USA. (4) Department of Dermatology, Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China. (5) Yale Cancer Center, Yale School of Medicine, New Haven, CT 06520, USA. (6) Breast Medical Oncology, Yale Cancer Center, Yale University, New Haven, CT 06520, USA. (7) Yale Stem Cell Center, Yale School of Medicine, New Haven, CT 06520, USA. (8) Yale Center for Immuno-Oncology, Yale School of Medicine, New Haven, CT 06520, USA.
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Citation: Sci Transl Med 2022 Feb 2