Breakthrough in Triple-Negative Breast Cancer: Targeting EZH2 to Halt Metastasis
Triple-negative breast cancer (TNBC) remains one of the most aggressive and hard-to-treat forms of breast cancer. A new preclinical study from Weill Cornell Medicine proposes a surprising and hopeful strategy: inhibiting an enzyme called EZH2 to prevent cancer cells from disseminating to distant organs by restoring orderly cell division and chromosomal stability.
Published on October 2 in Cancer Discovery, the research led by Dr. Vivek Mittal and colleagues uncovers a mechanistic link between EZH2 overactivity, chromosomal instability, and metastasis in TNBC. The findings challenge the prevailing idea that increasing chromosomal chaos in cancer cells should be exploited to trigger cell death, offering instead a strategy focused on restoring balance to cell division.
Understanding the Metastatic Seed: Why a Small Subset of TNBC Cells Drives Spread
Approximately 5% of cells within a TNBC tumor are most prone to metastasize. These cells exhibit distinct features, including altered metabolism and epigenetic changes—modifications to DNA packaging that do not alter the genetic code itself. The Weill Cornell team identified EZH2 as a potentially triggering factor for this metastatic subpopulation.
Analysis of patient data revealed that higher EZH2 levels correlated with greater chromosomal alterations in tumor cells. This observation guided laboratory experiments that tested whether lowering EZH2 activity could stabilize chromosome segregation during cell division, thereby reducing metastatic potential.
From Epigenetics to Chromosomal Stability: The Mechanistic Chain
EZH2 is an epigenetic regulator that normally modulates how DNA is packaged in cells. In TNBC, overproduction of EZH2 silences key genes needed for correct chromosome separation. The team found that EZH2 dampens tankyrase 1, a protein essential for ensuring proper chromosomal mechanics during division. With tankyrase 1 suppressed, CPAP accumulates, triggering excess centrosome activity. This cascade leads to abnormal cell divisions and an increase in tripolar or multipolar daughter cells, fueling chromosomal instability and, in turn, metastasis.
Blocking EZH2 Restores Order and Reduces Metastasis
Crucially, the researchers demonstrated that pharmacologically inhibiting EZH2 with tazemetostat—an FDA-approved drug for other cancers—reduced chromosomal instability in TNBC cell lines. Conversely, artificially increasing EZH2 levels augmented chromosomal errors. In mouse models, tumors with elevated EZH2 and chromosomal instability produced more lung metastases than tumors without EZH2, cementing a direct link between EZH2, instability, and metastatic spread.
Importantly, EZH2 inhibitors appeared to restore balance to the division machinery, significantly dampening metastatic spread in preclinical models. As Dr. Bai noted, this work is the first to connect an epigenetic regulator like EZH2 to chromosomal instability in a clear, mechanistic way. The therapeutic implication is that by targeting EZH2, clinicians may be able to intercept metastasis at its root.
Clinical Implications and Future Directions
Experts emphasize that EZH2 inhibitors could offer a new therapeutic avenue for TNBC and potentially other cancers characterized by chromosomal instability, such as certain lung cancers. Dr. Mittal and colleagues are exploring safety assessments and planning collaborations to initiate clinical trials to test EZH2 inhibitors in high-risk breast cancer patients. While repurposing tazemetostat remains a possibility, the door is open for other EZH2-targeted therapies that may prove more effective or better tolerated in TNBC.
“Metastasis is the main reason patients with triple-negative breast cancer face poor survival odds,” said Dr. Mittal. “Our study suggests a new therapeutic approach to block metastasis before it starts and help patients overcome this deadly cancer.” Dr. Bai added that this discovery links epigenetic regulation to chromosomal stability in a mechanistic fashion, offering a hopeful route to improved outcomes.
Broader Impact: A New Paradigm in Cancer Treatment
By reframing how researchers think about treating chromosomal instability, this work highlights the potential of stabilizing the cell division process as a strategy to suppress metastasis. If validated in clinical trials, EZH2 inhibitors could become part of a precision medicine approach for TNBC, enabling patients to live longer, with better quality of life, and with a reduced risk of metastatic relapse.
