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Two new possible drug targets for triple negative breast cancer

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The suppression of two genes reduces breast cancer tumor formation and spread by interfering with blood vessel formation and recruitment, according to new research from Houston Methodist, Weill Cornell Medical College and other institutions. The findings in the Proceedings of the National Academy of Sciences may help medical researchers identify effective drug targets for triple negative breast cancer (TNBC).

The genes, MLF2 (myeloid leukemia factor 2) and RPL39 (a ribosomal protein), were found to most profoundly affect the production of nitric oxide synthase, which helps regulate blood vessel behavior and could be crucial to the recruitment of new blood vessels to growing tumors. These genes influence the spread of TNBC throughout the body, and have not so far been linked with breast cancer.

"We have found two unique genes that may affect the most lethal type of breast cancer," said principal investigator and Houston Methodist Cancer Center Director Dr. Jenny Chang, who is also a professor of medicine at Weill Cornell Medical College. "Most importantly, by knowing how these genes function, we have drugs that can block nitric oxide signaling."

About 42,000 new cases of triple negative breast cancer are diagnosed in the United States each year, about 20 percent of all breast cancer diagnoses. Patients typically relapse within one to three years of being treated. TNBC is distinguished from other breast cancers in that it does not express the genes for estrogen receptors, progesterone receptors, and Her2/neu and is frequently harder to treat than other forms of the disease.

By suppressing close to 500 TNBC-related genes, Chang's group found interference was strongest with MLF2 and RPL39 in triple negative breast cancer model tissue. The scientists also learned that mutations in these genes in human patients were associated with worse survival in triple negative breast cancer patients.

The researchers went a step further, determining which configurations of small inhibitory RNA (siRNA) were most efficient at shutting down MLF2 and RPL39 in breast cancer stem cell lines. siRNA molecules interfere with the cell's ability to express genes and have proven to be effective drug tools for a wide variety of diseases, including some cancers.

In preliminary studies, the combination of siRNA and chemotherapy agent docetaxel significantly reduced tumor volume relative to chemotherapy alone and also appeared to prolong survival. Separate analyses showed suppression with siRNA appeared to yield fewer metastases to lung tissue.

Clinical trials of drugs that target the pathways that may cause TNBC to spread “have potential to significantly impact this highly aggressive form of breast cancer," Dr. Chang said.

Weill Cornell's Drs. Vivek Mittal, Xi Chen, and Steven S. Gross co-authored the study. Scientists from Five3 Genomics, Chan Soon-Shiong Institute for Advanced Health, Chan Soon-Shiong Institute for Advanced Health, and University of Texas M.D. Anderson Cancer Center also contributed.

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