Triple-negative breast cancer (TNBC) is one of the most aggressive and difficult-to-treat forms of breast cancer, but a new study led by Weill Cornell Medicine reveals a surprising way to stop its spread. Researchers have discovered that an enzyme called EZH2 stimulates TNBC cells to divide abnormally, allowing them to spread to distant organs. The preclinical study also found that drugs that block EZH2 can normalize cell division and prevent the spread of TNBC cells.
Targeting EZH2 to Contain Cancer
“Metastases are the main reason why patients with triple-negative breast cancer have poor survival,” said lead author Dr. Vivek Mittal, Ford-Isom Research Professor of Cardiothoracic Surgery and a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine. “Our study suggests a new therapeutic approach to block metastases before they develop and help patients overcome this deadly cancer.”
The findings, published in Cancer Discovery, challenge the widely held notion that cancer treatments should amplify the cell division errors already occurring in tumor cells beyond the breakpoint to induce cell death. When normal cells divide, the chromosomes – DNA “packets” that carry genes – are duplicated and split evenly between two daughter cells. This process gets mixed up in many cancer cells, leading to chromosomal instability: too many, too few or mixed-up chromosomes in several daughter cells. “I find trying to push cancer cells over the edge with more chromosomal instability somewhat concerning, because if you don’t get it right, it can paradoxically lead to aggressive disease,” Dr. Mittal said. “Instead, our results suggest that restoring order to cell division by targeting EZH2 can stop it from spreading.” First author Dr. Shelley Yang Bai began this work as a graduate student and is now a postdoctoral fellow with Dr. Mittal in Cardiothoracic Surgery at Weill Cornell Medicine. Dr. Samuel Bakhoum, who was at Memorial Sloan Kettering Cancer Center at the time, co-led this study.
Link Between Epigenetics and Metastasis
About 5% of cells in a TNBC primary tumor are highly likely to metastasize, and these cells have unique characteristics, such as different metabolism, increased chromosomal instability, and altered epigenetics – modifications to DNA or associated proteins that do not directly alter the genetic code. Dr. Mittal’s team found a suspect trigger that could initiate metastasis in these particular cancer cells: EZH2. This protein normally modifies the way DNA is packaged in cells. However, cancers often hijack EZH2 by increasing its production. In TNBC, this overproduction leads to the silencing of important genes required for the proper separation of chromosomes during cell division and to massive errors.
When analyzing data from breast cancer patients, Dr. Bai found that patients with higher levels of EZH2 also had tumor cells with more chromosomal alterations. This provided clues for further laboratory experiments. While inhibiting EZH2 with tazemetostat, an FDA-approved drug for the treatment of certain cancers, reduced chromosome instability in cell lines, genetically increasing EZH2 levels led to increased errors in cell division. In addition, mouse models with elevated EZH2 levels and chromosomal instability in primary tumors showed increased lung metastases compared to tumors without EZH2, confirming a direct link between EZH2 levels, chromosomal instability and metastasis. But how did EZH2 cause the instability?
The team discovered that EZH2 silences the Tankyrase-1 gene, which normally ensures that the chromosome segregation mechanism works properly during cell division. This triggers a chain reaction – the decrease in Tankyrase 1 causes another protein called CPAP to over-accumulate. This causes the cell’s centrosomes – structures that pull chromosomes apart – to proliferate uncontrollably, causing defective divisions into three or more daughter cells. The team showed that inhibiting EZH2 restored balance and significantly reduced metastasis in preclinical models. “For the first time, we have linked EZH2, an epigenetic regulator, to chromosomal instability in a mechanistic way,” said Dr. Bai.
Clinical Trials Testing EZH2 Inhibitors in High-Risk Breast Cancer
EZH2 inhibitors may be the first drugs that can directly suppress chromosomal instability. “This study offers a promising new approach to treating triple-negative breast cancer by targeting the cause of metastases,” said Dr. Magdalena Plasilova, associate professor of clinical surgery (pending appointment), surgical oncologist at NewYork-Presbyterian/Weill Cornell Medical Center and co-author of the study. “I see firsthand the devastating impact of metastatic disease on patients, and this offers hope for improved outcomes and survival rates.” While tazemetostat could be repurposed as a treatment for TNBC, other drugs could have similar or better effects. According to the researchers, this discovery opens the door for clinical trials to test EZH2 inhibitors in high-risk breast cancer and potentially other cancers that are also characterized by chromosomal instability, such as lung adenocarcinoma.