Cecilia Lee

Yale researchers found that the epigenetic regulator gene cat eye syndrome chromosome region candidate 2, or CECR2, is responsible for driving breast cancer metastasis –– making it exponentially more difficult to treat.

In a paper published in the journal Science Translational Medicine last month, researchers at the School of Medicine led by Qin Yan, who heads the Genetics, Genomics and Epigenetics program at the Yale Cancer Center, identified CECR2 as an epigenetic enhancer of metastatic breast cancer. Furthermore, they connected CECR2 with the altered immune system associated with metastasis, which features a higher amount of M2 macrophages. As tumor cells migrate from primary organs to other regions of the body, they have an altered environment around them called the tumor microenvironment. Immune cells, such as macrophages, contribute to this microenvironment to help sustain tumor survival and proliferation.

“This paper is one of a number that have been attempting to explain what the changes are in a cell when it becomes not just cancerous but spreads from one region to another in a process called metastasis,” co-leader of genetics, genomics and epigenetics at the Yale Cancer Center Jeffrey Townsend said. “This paper provides some outstanding findings that will potentially lead to pharmacological breakthroughs targeting CECR2 to prevent or treat breast cancer metastasis.”

In their paper, Yan’s team compared the expressed genetic information of primary and metastatic breast tumors and found that CECR2 expression was altered in the metastatic samples. Among 13 epigenetic factors correlated with an increased amount of M2 macrophage, CECR2 was a top upregulated gene.

Following the identification of CECR2 as a potential driver, the researchers established that CECR2 is critical for migration and invasion through tissue basement membranes, which are key steps of metastasis. Using cell lines, researchers found that cells lacking CECR2 have a two to threefold lower capability of migration and invasion. When these knockout cells were injected into tumor-bearing mice, it increased their survival and decreased the capability of cells to metastasize to another organ.

“CECR2 is known to be associated with cat eye syndrome, a rare chromosomal disorder that has nothing to do with cancer,” Yan said. “Because of its association with the tumor immune microenvironment and recent advances in immunotherapy for cancer patients, this is a promising target for long-term treatment.”

To investigate the underlying molecular mechanisms by which CECR2 drives breast cancer metastasis, Yan’s team examined downregulated and upregulated genes in CECR2 knockout cells. Such analysis revealed that knocking out CECR2 downregulates pathways such as epithelial-mesenchymal transition, or EMT, and tumor necrosis factor–α, or TNF-α, signaling by NF-κB. EMT enables cancer cells to suppress their epithelial features and adopt mesenchymal characteristics in order to successfully migrate and invade distant tissues. As such, its association with CECR2 further supports the role of CECR2 as a driver of metastasis.

To assess the therapeutic potential of CECR2-targeted therapy, mice were treated with a highly potent and specific CECR2 inhibitor called NVS-CECR2-1. The researchers found that treatment with NVS-CECR2-1 strongly inhibited the ability of cells to metastasize to the lungs, supporting potential treatments that target CECR2.

Computational biologist and data scientist at Verinomics and instructor of the undergraduate seminar “The Human Genome” Christopher Fragoso said that their gene of interest, CECR2, displayed only borderline differential expression.

“If the tumor samples were heterogeneous, maybe [the use of] additional replicates … could increase their ability to detect differences in expression,” Fragoso wrote in an email to the News. “Although differential expression alone didn’t provide as much support for their other arguments, like correlation with macrophage levels and co-expression with gene families of interest, the knockout of CECR2 provided additional evidence of the role of CECR2 in metastasis.”

Overall, both Fragoso and Townsend lauded the paper’s establishment of CECR2 as a driver and potential therapeutic target for breast cancer patients. As for potential areas of research in the future, Yan’s team hopes to understand how CECR2 works on a molecular level, building on previous studies that point to its interactions with chromatin structure.

According to the Centers for Disease Control and Prevention, breast cancer is the second most common form of cancer among women in the United States.

Veronica Lee covers breakthrough research for SciTech. She is a sophomore in Branford College majoring in molecular, cellular, and developmental biology.