Inhibition of the CECR2 gene prevents triple-negative breast cancer from advancing or metastasizing, a new study by researchers at Yale Cancer Center shows. The discovery could be an early step in finding new therapeutics for this type of cancer, a very difficult disease to treat. The findings are published this week in Science Translational Medicine.
“These study results are very encouraging as there are few effective treatments for triple-negative breast cancer once it has metastasized,” said senior study author Qin Yan, associate professor of Pathology and Director of Center for Epigenetics and Biomarkers in the Department of Pathology at Yale School of Medicine and co-director of Center for Breast Cancer of Yale Cancer Center. “We are constantly searching for new effective therapeutic strategies to help patients with this potentially deadly disease.”
Breast cancer is the most common cancer among women worldwide and the second leading cause of cancer death in the United States. Triple negative breast cancer does not express the receptors for estrogen, progesterone, or the human epidermal growth factor type 2 (HER2). Since there are no markers to reliably classify such tumors, they can’t yet be treated with targeted therapies. However, these patients do not carry a uniformly dismal prognosis. That observation, coupled with data coming from pathology and epidemiology, suggests that triple negative breast cancer is not a single clinical entity, but several.
“We don’t know how many subtypes of triple negative breast cancer there are,” Yan told Inside Precision Medicine, “and many of them are responsive to chemotherapy.” But there are often malignant cells left over even after surgery, and doctors would like to be able to eradicate those with appropriately targeted therapies.
In this study, researchers profiled 13 pairs of primary and metastatic breast tumor. By analyzing the transcriptomes of the samples, they found that distant metastases are more immune inert compared to matched primary tumors. The metastatic tumors also showed increased M2 macrophages.
The acetyl-lysine reader, cat eye syndrome chromosome region candidate 2 (CECR2), was the top up-regulated epigenetic factor associated with metastases and an increase in M2 macrophages. It was also associated with worse metastasis-free survival.
Cancer metastasis is a multistep process that involves cross-talk between cells in the tumor microenvironment. One of the major immune cell types in the breast tumor microenvironment, tumor-associated macrophages, promote breast tumor growth and metastasis and are associated with poor survival. Classically activated M1 macrophages have a proinflammatory role, while alternatively activated M2 macrophages are immunosuppressive.
The research team found that CECR2 allowed the breast cancer cells to migrate and invade to adjacent tissues and evade surveillance by the host immune system. CECR2 targeting resulted in the activation of T cells and prevented the tumor from spreading.
They also discovered that small molecule inhibitors of CECR2 can suppress the ability of triple negative breast cancer cells to spread in cell cultures and animal models, providing a possible new avenue of therapeutic strategy to treat advanced disease. According to researchers, the findings could lead to better response to current immunotherapies, which have had modest efficacy on breast cancer as monotherapies.
“There are small molecules that target CECR2 that can be used as tools for laboratory studies,” Yan told IPO. “But we need small molecule drugs that we can test in humans.”
Yan and his colleagues think the microenvironment is key to finding ways to target this cancer.
“We will continue to study these important findings,” added Yan. “We are working on characterizing the mechanisms by which CECR2 modulates gene expression and tumor microenvironment using multiple cutting-edge technologies. In addition, we hope to develop small molecule inhibitors of CECR2 for clinical studies.”
