In triple-negative breast cancer, approximately 5% of the primary tumor cells have a unique characteristic: they are highly prone to metastasizing. These cells share a distinctive trait: high levels of EZH2, an enzyme that normally regulates DNA packaging. But in tumors, EZH2 is overproduced and begins to silence genes key to proper cell division.
The researchers of the Weill Cornell Medicine They discovered that this silencing triggers a chain of molecular events that leads to uncontrolled centrosome multiplication and chromosomal instability, perfect conditions for tumor cells to spread to distant organs.
EZH2, How an Epigenetic Enzyme Wreaks Havoc
EZH2 is a kind of “molecular switch” that is part of a group of proteins called PRC2 complexIts job is to attach small "chemical signals" (methyl groups) to a protein called histone H3, around which the DNA is wound like a spool. When EZH2 places these signals at a specific point (lysine 27), the nearby stretch of DNA is turned off: the gene no longer functions, even though the DNA sequence remains identical. In essence, EZH2 doesn't change the DNA, but makes it temporarily inaccessible.
The problem arises when EZH2 overloads. Studies published on Journal of Hematology & Oncology They demonstrate that the enzyme is overexpressed in various tumors, from melanoma to lung cancer, from bladder cancer to endometrial cancer. But it is in triple-negative cancer that its role becomes particularly insidious.
The study conducted by the team of Vivek Mittal at Weill Cornell Medicine, published in CancerDiscovery, analyzed data from breast cancer patients and found a direct correlation: those with higher levels of EZH2 also showed more chromosomal alterations in their tumor cells. A sign that something, at the molecular level, was going awry.
The molecular cascade that leads to metastasis
Researchers have reconstructed the mechanism step by step. When EZH2 is overproduced, it silences the gene. tankyrase 1, which normally ensures that centrosomes (the structures that separate chromosomes during cell division) function properly. Without tankyrase 1, another protein called CPAP begins to accumulate. And when CPAP reaches too high levels, centrosomes multiply uncontrollably.
Instead of two centrosomes per cell, three, four, or five appear. The result is defective cell division: instead of generating two identical daughter cells, the parent cell produces three or more cells with randomly distributed chromosomes. Some receive too many chromosomes, others too few. This is chromosomal instability. And that's exactly what a tumor needs to adapt, resist drugs, and migrate.
Drugs that block EZH2 already exist
The good news is that inhibiting EZH2 is possible. tazemetostat, an FDA-approved drug for follicular lymphoma and epithelioid sarcoma, specifically blocks the enzymatic activity of EZH2. Recent clinical studies, including one published in January 2025, have tested combinations of tazemetostat with the immunotherapy pembrolizumab in patients with head and neck cancer, demonstrating tolerability and safety.
In mouse models of triple-negative breast cancer, blocking EZH2 significantly reduced lung metastasis. Tumor cells, deprived of their chromosomal instability mechanism, lost the ability to adapt and migrate. According to AIRC, EZH2 inhibitors represent one of the most promising frontiers of epigenetic therapy against cancer.
Triple negative affects approximately 8.000 women per year in Italy, representing 15% of all breast tumorsIt is one of the most aggressive forms: it lacks receptors for estrogen, progesterone and HER2, so hormone therapies and targeted anti-HER2 drugs do not work. According to the Veronesi FoundationImmunotherapy combined with chemotherapy has increased the five-year survival rate to 86% in early-stage cancer. But new strategies are still needed for metastatic disease.
Why blocking chaos works better than increasing it
There's a debate in oncology: should we push chromosomal instability beyond its limits, to the point of causing tumor cells to collapse? Or is it better to restore order? Vivek Mittal is clear:
"Finding the right level of chaos to kill cells is tricky. If you don't get it right, you risk making the tumor more aggressive. Restoring order by blocking EZH2 is safer and more effective."
Clinical trials testing EZH2 inhibitors in triple-negative cancer are already underway. The goal is to administer the drug to patients at high risk of metastasis—those with elevated EZH2 levels in their primary tumor—to block the spread before it even begins.
An epigenetic enzyme, a silenced gene, a protein that accumulates, centrosomes that multiply, chromosomes distributed randomly. And finally, metastasis. The chain is long, but there's only one switch. Blocking it could change the course of triple-negative breast cancer.
The drugs exist. Now trials are needed to demonstrate that they work in patients as well.
