Posted October 13, 2023

Qin Yan, Ph.D., Yale University

Despite advances in therapies, metastasis remains the leading cause in breast cancer-associated deaths. Given the pressing need to identify new drug targets and treatments for metastatic breast cancer, one area researchers are investigating is how epigenetic changes (i.e., alterations in DNA that do not involve changes to the underlying sequence) contribute to activation of pro-metastatic genes and processes, and whether epigenetic regulators can be explored for targeting tumor cells and their microenvironment. One epigenetic regulator of interest is cat eye syndrome chromosome region candidate 2 (CECR2), which has been shown to play important roles in numerous functions including DNA damage responses, although its specific functions in cancer (including metastasis) are not fully understood.

With support from a fiscal year (FY) 2014 Breast Cancer Research Program (BCRP) Era of Hope Scholar Award, Dr. Qin Yan and his team examined differences in gene expression among matched primary breast tumors and metastases from patients to reveal epigenetic regulators of breast cancer metastasis and identify potential therapeutic targets. The team found numerous differentially expressed genes, with metastatic samples having downregulated immune-related pathways and anti-tumor responses. A closer examination of the composition of immune cells found in the tumor microenvironment revealed a decrease in pro-inflammatory M1 macrophages and an increased ratio of M2 macrophages (which are immunosuppressive) to total macrophages. When Dr. Yan and his team analyzed the correlation of the M2 macrophage ratio with expression of epigenetic factors, CECR2 was found to be a top epigenetic factor whose expression was associated with poor metastasis-free survival.

To determine the role of CECR2 in metastasis in vivo, the team studied cell lines with CECR2 knockout (or control) in two mouse models of breast cancer. In these models, CECR2 knockout cells formed about 50% of metastatic lesions as controls, and metastatic potential to the lungs was decreased by 5- to 6-fold. In an immunocompetent mouse model, CECR2 knockout decreased lung metastasis by 38-fold, demonstrating the large influence the immune system has on metastatic tumor development. Analysis of the CECR2 knockout cells showed that CECR2 activates nuclear factor kappa B (NF-κB) response genes by interacting with acetylated v-rel avian reticuloendotheliosis viral oncogene homolog A (RELA), an NF-κB family member, through its bromodomain protein. Treatment with a CECR2 bromodomain inhibitor in metastatic breast cancer models reduced their M2 macrophage polarization as well as migration and invasion capabilities (compared to the control) both in vitro and in vivo, demonstrating CECR2’s potential as a druggable target for metastatic breast cancer.

From these studies, Dr. Yan and his team identified CECR2 as an epigenetic regulator of breast cancer and promising therapeutic target for breast cancer metastasis. CECR2 was found to promote cellular migration and invasion processes, most notably through recruitment of the immunosuppressive M2 macrophages. Taken together, the findings from Dr. Yan and his team support the potential utility of CECR2 bromodomain inhibition as a therapeutic strategy for the treatment of metastatic breast cancer. With support from an FY20 BCRP Breakthrough Award – Funding Level 2, Dr. Yan is continuing the development of CECR2 bromodomain inhibition therapeutic strategies with a focus on triple-negative breast cancer.

Publication:
Zhang M, Liu ZZ, Aoshima K, et al. 2022. CECR2 drives breast cancer metastasis by promoting NF-κB signaling and macrophage-mediated immune suppression. Science Translational Medicine 14(630):eabf5473. https://doi.org/10.1126/scitranslmed.abf5473.

Links:
Public and Technical Abstracts: Epigenetic Mechanisms of Breast Cancer Metastasis

Public and Technical Abstracts: Targeting a Bromodomain Protein, CECR2, in Breast Cancer

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