ddn Cancer Research News Exclusive: Doubling down on triple negatives
by Kelsey Kaustinen  |  Email the author


NEW YORK—Triple negative breast cancer is well known as one of the most aggressive cancer types, with some of the worst recurrence rates due to its metastatic tendencies, and accounts for 15 to 25 percent of all breast tumors. All breast cancers are prone to metastasis, and given their proximity to the lymph nodes, it is a serious issue in terms of treating these diseases. Fortunately, some of the latest work to come out of Weill Cornell Medical College consists of the discovery of the molecular trigger responsible for metastasis in triple negative breast cancer cells. The paper detailing the work, "Suppression of miRNA-708 by Polycomb Group Promotes Metastases by Calcium-Induced Cell Migration," appeared in Cancer Cell.  
The researchers were looking for a microRNA (miRNA)—small, non-coding RNA responsible for regulating gene expression—that targets metastasis without an affect on primary tumor growth, and found one in miR-708. The molecule is epigenetically inhibited in metastatic triple negative breast cancer, but when functioning properly, it acts as a metastatic tumor inhibitor, and tumors do not spread or form macrometastases.
"Metastasis can be lethal, and our findings point to potential targeted treatments to stop the spread of this aggressive breast cancer, " Dr. Vivek Mittal, an associate professor of cell and developmental biology and director of the Neuberger Berman Foundation Lung Cancer Research Laboratory at Weill Cornell Medical College, said in a press release. Mittal is the senior investigator for the study.  
Finding new treatment options for this aggressive form of breast cancer is particularly important given its poor outcome and lack of treatments. As triple negative breast cancer tumor cells lack the estrogen and progesterone hormone receptors in addition to HER2/neu growth factor, most breast cancer treatments, including the popular Herceptin, have little to no effectiveness.  
Mittal and his colleagues used genome-wide miRNA sequencing, which revelaed that miR-708 is largely down-regulated in this type of cancer. When not repressed, miR-708 suppresses neuronatin, a protein found on the membrane of the endoplasmic reticulum that controls how much calcium leaves the organelle. Mittal noted in a press release that calcium is what "provides legs to cancer cells to help them escape a tumor … If miR-708 is itself suppressed, there is an increase in production of neuronatin proteins, which then allows more calcium to leave the endoplasmic reticulum and activate a cascade of genes that turn on migratory pathways leading to metastasis."
The researchers tested miR-708's effectiveness in mouse models by delivering a synthetic form of the miRNA to triple negative breast cancer cells via bubbles of fat, and Mittal says the results were "astounding." Dr. Linda Vahdat, co-author of the study, agreed.
"These study results are terrific," said Vahdat, director of the Breast Cancer Research Program, chief of the Solid Tumor Service and professor of medicine at Weill Cornell Medical College and medical oncologist at the Iris Cantor Women's Health Center at NewYork-Presbyterian Hospital/Weill Cornell Medical Center, in a press release. "It not only offers us an avenue to treat metastatic triple negative breast cancer in the short-term, but also gives us the roadmap to prevent metastases in the long-run. We are anxious to get this into the clinic and are working as quickly as possible towards that end."  
The team found that miR-708 blocked the cancerous cells' metastatic outgrowth. They also found that miR-708 is repressed by polycomb repressor complex proteins, specifically histone-lysine N-methyltransferase EZH2, which is already being targeted by pharmacological agents as a potential treatment against lymphoma cancer cells.
"It is exciting that there are now drugs that can turn off the silencing of these critical genes. They could very well work for this aggressive breast cancer," said Mittal. "Finding that there may be a way to shut down the spread of an aggressive breast cancer—which is the only way that triple negative breast cancer can be controlled and lives spared—is very promising."
This approach's potential is not limited solely to triple negative breast cancer, either.
  "[miR-708] is also suppressed in the metastasis that is derived from any breast cancer," says Mittal. "But since triple negative's are highly metastatic, it makes more sense to try to focus on this group because there is no treatment for this particular subset of breast cancer. But definitely we are open to looking at miR-708 in other cancers as well."
Mittal says the team is also working to see if miR-708 can be reactivated in tumor cells by a protein or genetic trigger, and is looking for inhibitors that could counteract the miRNA's suppression. In addition to the work in epigenetic regulation, the researchers will be exploring the potential of miR-708 in direct delivery as a therapeutic. They are starting to think about clinical trials, he adds, and notes that they are "looking into partners on the development of this approach."  
Funding for the study came from the Neuberger Berman Lung Cancer Laboratory, the Robert I. Goldman Foundation and the Cornell Center on the Microenvironment and Metastasis through an award from the National Cancer Institute.
Code: E02151300

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