New findings link EZH2 to TNBC metastasis and chromosomal instability
Triple negative breast cancer (TNBC) remains one of the most challenging cancer types to treat, largely due to its propensity to spread to distant organs. A new preclinical study led by Weill Cornell Medicine uncovers a surprising mechanism: an enzyme called EZH2 drives abnormal cell division in TNBC cells, enabling metastasis. Importantly, drugs that block EZH2 can restore orderly cell division and blunt metastatic spread. The work, published in Cancer Discovery, points to a potential new therapeutic strategy aimed at preventing metastasis before it starts.
How EZH2 fuels chromosomal instability and metastasis
Most cancer cells already exhibit chromosomal instability, a condition where chromosomes are mismanaged during cell division, sometimes resulting in too many or too few chromosomes in daughter cells. In TNBC, researchers found that a subset of tumor cells—roughly 5%—are particularly prone to metastasis and possess unique metabolic and epigenetic features that set the stage for spread. EZH2, an epigenetic regulator, was identified as a key driver behind these changes.
Through analysis of patient data and a series of experiments, the team observed that high levels of EZH2 correlated with greater chromosomal alterations in tumor cells. In laboratory models, inhibiting EZH2 with tazemetostat reduced chromosomal instability. Conversely, increasing EZH2 levels amplified division errors. Mouse models further supported the link: tumors with elevated EZH2 and instability metastasized more frequently to the lungs than tumors without EZH2 overexpression.
The mechanistic chain: EZH2, tankyrase 1, CPAP, and centrosomes
The researchers traced the mechanism to a cascade triggered by EZH2. Normally, tankyrase 1 helps ensure proper chromosome separation during cell division. EZH2 silences the tankyrase 1 gene, which reduces tankyrase 1 activity. This leads to an unintended buildup of a protein called CPAP, which in turn causes centrosomes—the cellular structures that pull apart chromosomes—to proliferate uncontrollably. The result is faulty divisions that produce three or more daughter cells and contribute to chromosomal chaos that can fuel metastasis.
This study marks a significant shift in thinking: rather than forcing cancer cells into catastrophic division to kill them, restoring orderly mitosis by targeting EZH2 may prevent metastatic spread at its roots.
Clinical implications and future directions
Though tazemetostat is already FDA-approved for other cancers, its potential use in TNBC represents a promising repurposing avenue. The findings suggest EZH2 inhibitors could suppress chromosomal instability and curb metastasis, potentially improving survival for patients facing TNBC. Dr. Vivek Mittal, senior author and a leading cardiothoracic surgeon and cancer researcher, emphasizes that this approach targets the root cause of metastasis rather than simply slowing tumor growth.
Experts caution that translating preclinical results to patients requires careful evaluation of safety, dosing, and long-term effects. Dr. Bai, the study’s first author, notes that EZH2’s role as an epigenetic regulator means therapies must balance anti-tumor activity with maintaining normal cellular functions. Nevertheless, the research opens a clear path toward clinical trials testing EZH2 inhibitors in high-risk breast cancer and possibly other tumors marked by chromosomal instability, such as certain lung cancers.
Broader impact: epigenetics and metastasis
Beyond TNBC, this work contributes to a growing understanding of how epigenetic regulators influence metastasis through chromosomal dynamics. By pinpointing a mechanistic link between EZH2 and chromosomal instability, the study provides researchers with new biomarkers to identify patients at greatest risk of spread and new targets to interrupt the metastatic cascade.
Conclusion
The discovery that EZH2 drives chromosomal instability and metastasis—and that its inhibition can restore chromosomal order—offers a hopeful new strategy for tackling TNBC. As clinical trials loom, patients and clinicians alike will watch closely to see whether EZH2 inhibitors can translate this preclinical promise into real-world advances against this aggressive breast cancer subtype.
