Triple negative breast cancer (TNBC) is one of the most aggressive and hardest forms of breast cancer to treat, but a new study led by Weill Cornell Medicine suggests a surprising way to stop it from spreading. Researchers have discovered that an enzyme called EZH2 drives TNBC cells to divide abnormally, which enables them to relocate to distant organs. The preclinical study also found drugs that block EZH2 could restore order to dividing cells and thwart the spread of TNBC cells.
"Metastasis is the main reason patients with triple negative breast cancer face poor survival odds," said senior author Dr. Vivek Mittal, Ford-Isom Research Professor of Cardiothoracic Surgery and member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine. "Our study suggests a new therapeutic approach to block metastasis before it starts and help patients overcome this deadly cancer."
The findings, published Oct. 2 in Cancer Discovery, challenge the popular notion that cancer treatments should boost cell division errors already occurring in tumor cells beyond the breaking point to induce cell death. When normal cells divide, the chromosomes -- DNA "packages" carrying genes -- are duplicated and split evenly into two daughter cells. This process goes haywire in many cancer cells, leading to chromosomal instability: too many, too few, or jumbled chromosomes in multiple daughter cells.
"I find the attempt to drive cancer cells over the edge with more chromosomal instability a little concerning because if you don't reach the right level, it may paradoxically lead to aggressive disease," Dr. Mittal said. "Instead, our findings suggest that restoring order to cell division by targeting EZH2 can stop them from spreading."
First author Dr. Shelley Yang Bai began this work as a graduate student and is now a postdoctoral associate 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.
Linking Epigenetics and Metastasis
About 5% of cells in a TNBC primary tumor are highly likely to metastasize, and these cells have unique features such as different metabolism, increased chromosomal instability and altered epigenetics -- modifications to DNA or its associated proteins that do not directly change the genetic code.
Dr. Mittal's team found a suspicious culprit that could be triggering metastasis in these particular cancer cells: EZH2. This protein normally modifies how DNA is packaged in cells. But cancers often hijack EZH2 by increasing its production. In TNBC, this overproduction leads to the silencing of key genes needed for chromosomes to segregate properly during cell division and to rampant 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 lab experiments. While inhibiting EZH2 with tazemetostat, an FDA-approved drug to treat certain cancers, reduced chromosomal instability in cell lines, boosting EZH2 levels genetically increased errors in cell division.
Furthermore, mouse models with elevated EZH2 and chromosomal instability in primary tumors showed increased lung metastases compared to tumors lacking EZH2, confirming a direct link between EZH2 levels, chromosomal instability and metastasis. But how was EZH2 driving instability?
Chromosomal Chaos
The team discovered that EZH2 silences the tankyrase 1 gene, which normally ensures the chromosome-separating machinery works properly during cell division. This triggers a chain reaction -- the decrease in tankyrase 1 causes another protein called CPAP to build up excessively. This prompts the cell's centrosomes -- structures that pull chromosomes apart -- to multiply uncontrollably, leading to faulty divisions into three or more daughter cells.
The team showed that inhibiting EZH2 restored balance, significantly reducing metastasis in preclinical models. "For the first time, we have linked EZH2, which is an epigenetic regulator, with chromosomal instability in a mechanistic fashion," Dr. Bai said.
EZH2 inhibitors may be the first drugs that can suppress chromosomal instability directly. "This study provides a promising new approach to treating triple-negative breast cancer by targeting the root cause of metastases," said Dr. Magdalena Plasilova, associate professor of clinical surgery (pending appointment at rank), a surgical oncologist at NewYork-Presbyterian/Weill Cornell Medical Center and an author on the study. "I see firsthand the devastating impact of metastases on patients, and this offers hope for improved outcomes and survival rates."
While Tazemetostat could be repurposed as a treatment for TNBC, other drugs might have similar or better effects. "Our discovery opens the door for clinical trials to test EZH2 inhibitors in high-risk breast cancer and potentially other cancers that are also marked by chromosomal instability, such as lung adenocarcinoma," said Dr. Mittal, who is also a member of the Englander Institute of Precision Medicine at Weill Cornell. Currently, he is planning collaborations to conduct safety tests in a clinical trial.