New findings link EZH2 to chromosomal chaos and metastasis in TNBC
Triple-negative breast cancer (TNBC) remains one of the most challenging cancer types to treat due to its aggressive nature and lack of targeted hormones. A groundbreaking preclinical study from Weill Cornell Medicine, published in Cancer Discovery, identifies a surprising driver of TNBC metastasis and demonstrates a potential strategy to stop it in its tracks. The research centers on EZH2, an epigenetic enzyme that, when overexpressed, perturbs how cancer cells divide and spread to distant organs.
How EZH2 fuels chromosomal instability and metastasis
In healthy cells, chromosomes are faithfully copied and equally divided during cell division. In many TNBC cells, this process goes awry, leading to chromosomal instability that fosters aggressive behavior and metastatic capacity. The Weill Cornell team found that EZH2 overproduction silences the tankyrase 1 gene, a key player in maintaining the chromosome-separating machinery. The downstream effect is a buildup of CPAP, which drives centrosomes to multiply abnormally. The result is tripolar or multipolar cell division and increased chromosomal chaos, a hallmark of highly metastatic cells.
Dr. Shelley Bai, the study’s first author, notes that these observations connect an epigenetic regulator to a concrete, mechanistic route for metastasis. “For the first time, we have linked EZH2, which is an epigenetic regulator, with chromosomal instability in a mechanistic fashion,” she explained. The team’s data from patient tumor analyses showed that higher EZH2 levels correlated with greater chromosomal alterations, supporting the laboratory findings.
Blocking EZH2 to restore order and prevent spread
The researchers tested an EZH2-inhibiting approach using tazemetostat, an FDA-approved drug for other cancers. In cell culture models, inhibiting EZH2 reduced chromosomal instability. Conversely, increasing EZH2 levels genetically amplified division errors. In mouse models, primary tumors with elevated EZH2 exhibited more lung metastases than tumors with normal EZH2, establishing a direct link between EZH2, chromosomal instability, and metastatic spread.
Crucially, pharmacologic EZH2 inhibition not only reduced instability but also diminished metastasis in preclinical models. Dr. Mittal emphasizes a shift in thinking: rather than pushing cancer cells toward lethal instability, restoring orderly division might thwart their ability to disseminate. “Our findings suggest that restoring order to cell division by targeting EZH2 can stop them from spreading,” he said.
Clinical implications and future directions
The study positions EZH2 inhibitors as potentially first-in-class agents to suppress chromosomal instability directly, addressing a root cause of metastasis in TNBC. While tazemetostat is already approved for other cancers, the researchers are exploring safety and efficacy in high-risk breast cancer settings and planning collaborations for early clinical evaluation. Dr. Magdalena Plasilova, a surgical oncologist involved in the study, underscored the clinical promise: this approach could improve outcomes and survival for patients facing metastatic risk.
Beyond TNBC, the team notes that chromosomal instability is a feature of other cancers, such as certain lung cancers. This raises the possibility that EZH2 inhibitors might benefit a broader patient population if the same mechanistic link holds. The next steps include initiating clinical trials to assess safety and potential benefits in humans, as well as refining patient selection to identify those most likely to respond to EZH2-targeted therapy.
What this means for patients and researchers
While still early, the study reframes how metastasis could be controlled in breast cancer. By targeting the root cause of chromosomal instability—the EZH2-driven silencing of tankyrase 1 and the subsequent centrosomal chaos—there is renewed hope for therapies that limit disease spread and improve survival for patients with TNBC. The research also highlights the value of epigenetic regulation as a therapeutic axis, offering a complementary strategy to conventional treatments that focus solely on tumor killing.
As the field moves toward clinical trials, clinicians, researchers, and patients alike will be watching closely to see whether EZH2 inhibitors can translate these preclinical successes into meaningful, real-world benefits for those confronting triple-negative breast cancer.
