ddn Cancer Research News Exclusive: Doubling down on triple negatives

Weill Cornell Medical College team discovers miRNA responsible for metastasis in triple negative breast cancer cells

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NEW YORK—Triple negative breast cancer is well known as oneof the most aggressive cancer types, with some of the worst recurrence ratesdue to its metastatic tendencies, and accounts for 15 to 25 percent of allbreast tumors. All breast cancers are prone to metastasis, and given theirproximity to the lymph nodes, it is a serious issue in terms of treating thesediseases. Fortunately, some of the latest work to come out of Weill CornellMedical College consists of the discovery of the molecular trigger responsiblefor metastasis in triple negative breast cancer cells. The paper detailing thework, "Suppression of miRNA-708 by Polycomb Group Promotes Metastases byCalcium-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 targetsmetastasis without an affect on primary tumor growth, and found one in miR-708.The molecule is epigenetically inhibited in metastatic triple negative breastcancer, 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 topotential targeted treatments to stop the spread of this aggressive breastcancer,
" Dr. Vivek Mittal, an associate professor of cell anddevelopmental biology and director of the Neuberger Berman Foundation Lung Cancer Research Laboratory at Weill Cornell Medical College, said in a press release. Mittal isthe senior investigator for the study.
Finding new treatment options for this aggressive form ofbreast cancer is particularly important given its poor outcome and lack oftreatments. As triple negative breast cancer tumor cells lack the estrogen andprogesterone hormone receptors in addition to HER2/neu growth factor, mostbreast cancer treatments, including the popular Herceptin, have little to noeffectiveness.
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 themembrane of the endoplasmic reticulum that controls how much calcium leaves theorganelle. Mittal noted in a press release that calcium is what "provides legsto 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 allowsmore calcium to leave the endoplasmic reticulum and activate a cascade of genesthat turn on migratory pathways leading to metastasis."
The researchers tested miR-708's effectiveness in mousemodels by delivering a synthetic form of the miRNA to triple negative breastcancer 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 ofthe Breast Cancer Research Program, chief of the Solid Tumor Service andprofessor of medicine at Weill Cornell Medical College and medical oncologistat the Iris Cantor Women's Health Center at NewYork-Presbyterian Hospital/WeillCornell Medical Center, in a press release. "It not only offers us an avenue totreat metastatic triple negative breast cancer in the short-term, but alsogives us the roadmap to prevent metastases in the long-run. We are anxious toget this into the clinic and are working as quickly as possible towards thatend."
The team found that miR-708 blocked the cancerous cells'metastatic outgrowth. They also found that miR-708 is repressed by polycombrepressor complex proteins, specifically histone-lysine N-methyltransferaseEZH2, which is already being targeted by pharmacological agents as a potentialtreatment against lymphoma cancer cells.
"It is exciting that there are now drugs that can turn offthe silencing of these critical genes. They could very well work for thisaggressive breast cancer," said Mittal. "Finding that there may be a way toshut down the spread of an aggressive breast cancer—which is the only way thattriple negative breast cancer can be controlled and lives spared—is verypromising." 
This approach's potential is not limited solely to triplenegative breast cancer, either. 
"[miR-708] is also suppressed in the metastasis that isderived from any breast cancer," says Mittal. "But since triple negative's arehighly metastatic, it makes more sense to try to focus on this group becausethere is no treatment for this particular subset of breast cancer. Butdefinitely 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 canbe reactivated in tumor cells by a protein or genetic trigger, and is lookingfor inhibitors that could counteract the miRNA's suppression. In addition tothe work in epigenetic regulation, the researchers will be exploring thepotential of miR-708 in direct delivery as a therapeutic. They are starting tothink about clinical trials, he adds, and notes that they are "looking intopartners on the development of this approach."
Funding for the study came from the Neuberger Berman LungCancer Laboratory, the Robert I. Goldman Foundation and the Cornell Center onthe Microenvironment and Metastasis through an award from the National CancerInstitute.

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