NEW YORK (Reuters Health) – CECR2 is an epigenetic driver of breast cancer metastasis, and inhibiting the protein prevented metastases in mouse models, researchers say.
“Two findings were quite surprising,” Dr. Qin Yan of Yale Cancer Center in New Haven told Reuters Health by email. “First, CECR2 had not been studied in cancer when we started to work on it. It is a gene that was amplified in patients with cat eye syndrome, with a variety of abnormalities including defects in the iris of the eye, and specific heart and kidney defects.”
“Second,” he said, “we found that an increase of CECR2 in tumor cells elicits tumor-supporting inflammatory responses in the metastatic sites, suggesting that the host immune response could be co-opted by the tumor cells for their growth.”
Dr. Yan and colleagues note in Science Translational Medicine, “Emerging evidence suggests that certain epigenetic and transcriptional regulators drive cancer metastasis and could be targeted for metastasis treatment.”
To identify such regulators of breast cancer metastasis, the team sequenced 13 matched pairs of primary breast tumors and metastases from patients.
Compared with the primary tumors, the metastases were more immune inert, with higher amounts of immune-suppressing M2 macrophages. CECR2 was the top up-regulated epigenetic regulator of metastases, associated with both an increased abundance of M2 macrophages and worse metastasis-free survival.
CECR2 was required for breast cancer metastasis in multiple mouse models. The protein activated the expression of multiple metastasis-promoting genes, such as TNC, MMP2, and VEGFA, as well as the cytokine genes CSF1 and CXCL1, which are critical for immunosuppression at metastatic sites.
Consistent with the lab findings, inhibiting CECR2 with the experimental compounds NVS-CECR2-1 or GNE-886 mitigated immune suppression at existing metastases and prevented breast cancer cells from spreading to the lungs in mice.
The authors conclude, “These results reveal that targeting CECR2 may be a strategy to treat metastatic breast cancer.”
Dr. Yan added, “We do not envision a downside to targeting CECR2, as it has specific effects on cancer cells that are spreading. We have not observed side effects in mice treated with a CECR2 inhibitor. The congenital effects observed in cat eye syndrome are because there is too much of it. Our findings could be used to treat this syndrome as well.”
Molecular biologist Dr. Yibin Kang of the Ludwig Institute for Cancer Research-Princeton at Princeton University in New Jersey told Reuters Health by email, “Metastatic cancers are often more resistant to treatments, although the biological basis of this phenomenon is poorly understood. This study identified…CECR2 as one of the underlying mechanisms of the more immune-inert microenvironment in metastatic sites compared to the primary tumors.”
“CECR2 inhibitors showed impressive therapeutic efficacy as a single agent when treatment was initiated at the time of tumor inoculation in preclinical models,” he said. “It will be interesting to test combinational therapies of CECR2 inhibitors with immune checkpoint blockade therapies in late-stage metastatic diseases, as this is the main hurdle in reducing mortality from cancer.”
“The study underscores once again the potential of epigenetic therapies in cancer,” Dr. Kang concluded.
SOURCE: https://bit.ly/3uwAb0x Science Translational Medicine, online February 2, 2022.