Breakthrough Treatment May Finally Slow One of the Most Lethal Forms of Breast Cancer

Triple negative breast cancer represents around 15 % of diagnosed cases, but it remains one of the deadliest. Its resistance to hormonal and targeted treatments makes it an urgent medical challenge, especially since its ability to form metastases early compromises the prognosis of patients. Contrary to traditional approaches seeking to cause the collapse of tumor cells by increasing their genetic instability, researchers from Weill Cornell Medicine and Memorial Sloan Kettering Cancer Center propose an opposite strategy.

Their work, published in the journal Cancer Discovery, reveal that it is possible to contain tumor dissemination by restoring an ordered functioning, in particular during the division of cancer cells. By targeting a key enzyme, EZH2, they open a therapeutic track which could transform the way in which certain aggressive forms of cancer are treated.

Triple negative, a form of cancer with high metastatic potential

Triple negative breast cancer (TNBC for Triple-Negative Breast Cancer) is defined by the absence of three receivers: estrogens, progesterone and HER2. This characteristic makes it insensitive to hormonal treatments and current targeted therapies. It affects approximately 15 % of patients with breast cancer. But it causes a significantly higher proportion of death. This discrepancy is explained in particular by its strong capacity to produce metastases, sometimes from the early stages of the disease.

TNBC cells often have high chromosomal instability. This means that their genetic material is often poorly distributed at the time of cell division. This fact promotes the appearance of more aggressive cell subpopulations. These errors provide an evolutionary advantage to cells capable of detaching from the primary tissue, to survive in the blood circulation, then to colonize new organs. It is this genetic drift that makes TNBC so difficult to treat.

According to the work carried out by Dr. Vivek Mittal (Weill Cornell Medicine), around 5 % of the cells present in primary TNBC tumors have distinct characteristics. They display a modified metabolism, higher genetic instability levels, and so -called “epigenetic” alterations. They modify the expression of the genes without touching the DNA sequence. These cells are therefore suspected of playing a driving role in the development of metastases.

Understanding the mechanisms that make them invasive therefore becomes crucial. The stake then is to prevent the spread of the tumor. A point that remains the main cause of death linked to TNBC.

EZH2, a silent engine of genetic chaos in tumor cells

The EZH2 enzyme (Enhancement of Zeste Homolog 2) is at the heart of recent research on triple negative breast cancer. It is methyltransferase, that is to say an enzyme that modifies the expression of genes via epigenetic processes. Concretely, it adds methyl groups to certain proteins associated with DNA (histones), resulting in the repression of essential genes.

In TNBC cells, EZH2 is frequently overexpimated. This hyperactivity causes the gene deactivation Tanke 1 (TNKS). This gene is involved in the regulation of centrosomes, key structures in cell division. Their role is to ensure a symmetrical separation of chromosomes during mitosis. However, in the absence of tank 1, a cascade of molecular events is triggered.

The removal of TNKS causes abnormal accumulation of the CPAP protein, itself involved in controlling the number of centrosomes. Result: the cells are found with an excess of these structures. This causes asymmetrical, even multipolar divisions. Instead of producing two daughter cells, the mother cell can generate three or four, each receiving an incorrect number of chromosomes.

This chromosomal instability feeds the aggressiveness of the TNBC. Transcriptomical and epigenomic analyzes, carried out in particular by Dr. Shelley Yang Bai, have shown a clear correlation between the overactivation of EZH2 and the amplification of mitotic errors. These dysfunctions contribute on the one hand to tumor growth. On the other hand, they participate in the emergence of clones capable of migrating and invading other fabrics. Genetic chaos therefore becomes a vector of cancer dissemination. Identify EZH2 as the central regulator of this drift offers a precise target and potentially therapeutic use.

Inhibit ezh2 to restore a controlled cell cycle

Based on the observation that the EZH2 enzyme triggers chromosomal instability via epigenetic mechanisms, the researchers tested if its inhibition would restore normal cellular operation. For this, they used Tazemetostat, a drug approved by the FDA for other types of cancers (including certain lymphomas). This compound specifically blocks the enzymatic activity of EZH2.

The experiments were first carried out on TNBC cell lines. Under treatment, the cells displayed a significant decrease in the number of supernumerary centrosomes, and a correction of errors during the separation of chromosomes. In parallel, the expression of the TNKS gene, previously repressed, dates back to normal levels. These results suggest that the treatment helps defuse the deleterious waterfall triggered by EZH2.

© Dr Shelly Yang Bai

Left: normal cellular division with chromosomes (blue) and two centrosomes (green). Right: During a defective cell division, an excessive number of centrosomes is present.

The effects were then tested in vivo on murine models. The mice carrying TNBC tumors treated with the Tazemetostat presented up to 65 % less pulmonary metastases than untreated mice. This figure marks a turning point. It shows that stabilization of the mitotic cycle can, by itself, limit tumor dissemination. And above all, it was obtained without provoking cell death, but by restoring an ordered operation.

Dr. Magdalena Plasilova, co-author of the study, underlines the importance of this approach in a press release. “” We target the very cause of metastases, not just the symptoms. This could transform the treatment of high -risk cancers ». By acting upstream of tumor spread, this strategy could significantly extend the survival of patients.

Towards targeted and preventive therapies for cancers with chromosomal instability

The scope of these discoveries exceeds the only framework of triple negative breast cancer. Chromosomal instability is a line shared by many aggressive cancers. In particular pulmonary carcinoma, certain cancers of the ovary or the pancreas. All have a disorganized cell division, conducive to genetic diversification and therefore resistance to treatments. In this sense, EZH2 represents a transverse therapeutic target.

What the study demonstrates is that it is possible to intervene not as a last resort, but upstream of the metastatic process. The idea is no longer to eliminate cells once they have migrated, but from preventing them from becoming mobile. This opens the way to clinical trials based not only on reducing the size of tumors, but also on the prevention of metastases as the main effectiveness criterion.

Other EZH2 inhibitors are being developed, some more specific or better tolerated than Tazemetostat. Combinations with immunotherapy or cellular control points inhibitors are also envisaged. The approach remains compatible with the principles of precision medicine. It targets patients identified as at high risk, on the basis of biomarkers such as EZH2's level of expression or chromosomal instability.

Dr. Mittal, who already provides clinical trials in collaboration with several institutes, insists on the need to adapt the protocols. “” We must review how we measure the success of a treatment. Preventing a cell from becoming metastatic is a goal as crucial as reducing a tumor ». This change of perspective could transform the strategy to combat several aggressive cancers, finally by targeting their ability to spread.

Source: Yang Bai, et al., “Epigenetic Regulation of Chromosomal Instabilities by Ezh2 Methyltransferase”. Discov Cancer 2025