The suppression of two genes reduce breast cancer tumor formation and metastasis by interfering with blood vessel formation and recruitment, report scientists from Houston Methodist and five other institutions in the Proceedings of the National Academy of Sciences (now online). The findings may help medical researchers identify effective drug targets for triple negative breast cancer, or TNBC.
The genes, MLF2 (myeloid leukemia factor 2) and RPL39 (a ribosomal protein), were found to most profoundly impact 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 impact 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 Jenny Chang, M.D., “Most importantly, by knowing how these genes function, we have drugs that can block nitric oxide signaling and will begin a clinical trial in the Cancer Center in the near future”
About 42,000 new cases of triple negative breast cancer (TNBC) 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 receptor, progesterone receptor, and Her2/neu and is frequently harder to treat.
By suppressing close to five hundred 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 (human) 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.
Earlier this year, Chang, Weill Cornell Medical College Dean Laurie Glimcher, M.D., and colleagues reported to Nature another possible drug target for TNBC patients called XBP1, another gene previously unassociated with breast cancer.
“Together with our colleagues in Weill Cornell, we are launching clinical trials that affect these unique novel pathways that may cause TNBC to spread. These trials have potential to significantly impact this highly aggressive form of breast cancer.”
Chang has a secondary affiliation with Weill Cornell Medical College as a professor of medicine. Also contributing to the PNAS paper were Bhuvanesh Dave, Sergio Granados-Principal, Rui Zhu, Haifa Shen, Xuewu Liu, Mauro Ferrari, Ming Zhan, Stephen T.C. Wong, and Muthiah Kumaraswami (Houston Methodist), Stephen Benz (Five3 Genomics), Shahrooz Rabizadeh and Patrick Soon-Shiong (Chan Soon-Shiong Institute for Advanced Health), Ke-Da Yu and Zhimin Shao (Shanghai Cancer Center and Cancer Institute of Fudan University), Xiaoxian Li and Michael Gilcrease (University of Texas M.D. Anderson Cancer Center), and Vivek Mittal, Xi Chen, and Steven S. Gross (Weill Cornell Medical College). The work was funded by grants from the National Cancer Institute (R01 CA138197, U54 CA149196), Golfers against Cancer, the Breast Cancer Research Foundation, Causes for a Cure, Team Tiara, the Emily W. Herrman Cancer Research Laboratory, the U.S. Department of Defense Innovator Expansion Award (BC104158), the Susan G. Komen for the Cure (KG 081694), and Fundacion Alfonso Martin Escudero (SGP)