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When a movie character says, 鈥淚t鈥檚 too quiet,鈥� that鈥檚 usually a sign something bad may happen.

Now, University of Florida researchers have discovered that when variations of a certain protein in our cells are too quiet, it may add to the risk that someone will develop lung cancer. When scientists restored the protein to its normal, active self, its cancer-inhibiting properties reappeared.

These discoveries, published in two reports in the online version of Oncogene, provide evidence that drugs can potentially suppress tumor growth by restoring cellular processes rather than inhibiting cancer-causing genes known as oncogenes.

鈥淚t鈥檚 a well-accepted fact that you can inhibit things, particularly oncogenes, that drive cancer. Oncogenes are the cancer鈥檚 gas pedal,鈥� said principal investigator David Reisman, M.D., Ph.D., a UF associate professor of medicine and a member of the UF Shands Cancer Center. 鈥淲hat we鈥檝e done is demonstrate the feasibility of reconstituting the cancer brake.鈥�

The protein, known as Brahma, or BRM, is involved in the regulation of cellular functions like gene expression, DNA repair, cell adhesion and telling cells whether to divide and grow or stop dividing and die. Other studies have found 鈥渟ilenced鈥� BRM is present in 10 to 20 percent of all solid tumors. Reisman knew from his own research in mouse models that silencing the BRM gene alone did not cause tumor growth, but when carcinogens were introduced, 10 times as many tumors appeared compared with mice with normal BRM expression.

鈥淭he gene was not a tumor suppressor in the classical definition but a tumor susceptibility gene, and when the expression is lost, it primes you to other events that potentiate the development of tumors, such as tobacco carcinogens,鈥� Reisman said.

More people die of lung cancer every year than of cancers of the breast, colon, prostate or lymphoma combined, according to the National Cancer Institute. However, only 10 percent of smokers develop lung cancer and as many as 15 percent of those diagnosed with lung cancer have never smoked.

Reisman鈥檚 work suggests the presence of two variations within the BRM gene 鈥� known as polymorphisms 鈥� could potentially be biomarkers for lung cancer and assist doctors in identifying individuals at higher risk, which could lead to more cost-effective screening practices and lifesaving early detection.

Study investigators sequenced the genes of 160 people and learned that roughly 20 percent carry the gene variants. With collaborator Geoffrey Liu, M.D., a research scientist at the Ontario Cancer Institute at the University of Toronto, the team then verified the presence of the silenced BRM variants in human lung tumors.

Reisman and Lui also conducted case control studies on 1,199 people who were matched for age, gender and smoking history but in whom 484 individuals had lung cancer and 715 were healthy and cancer free.

鈥淲e found these polymorphic sites were greatly enriched in the population that had developed lung cancer,鈥� Reisman said. 鈥淭he chance that you would develop lung cancer if you had both polymorphic sites was 220 percent higher. Our analysis demonstrated those odds to be independent of smoking history, sex, race and cancer type.鈥�

Reisman鈥檚 team also studied whether it would be possible to restore the normal expression of the BRM protein. Certain compounds, called histone deacetylase 鈥� or HDAC 鈥� inhibitors, had been demonstrated by other researchers to reactivate the BRM gene, but did not restore the normal, cancer-suppressing function of the BRM protein.

By introducing the healthy protein alongside the reactivated gene, the researchers were able to stop the growth of cancer cells. That makes the process a potential target for drug therapies to use in suppressing many tumor types.

鈥淲e know there are a lot of genes that are silenced in cancer, and it鈥檚 believed that gene silencing is necessary in order for the cancer to grow and thrive. This research demonstrates 鈥� and is really the first example of 鈥� an approach that鈥檚 led to the reactivation of a specific tumor-suppressing gene,鈥� said Aubrey Thompson, Ph.D., a professor of cancer biology at Mayo Clinic Comprehensive Cancer Center in Jacksonville, Fla., who was not involved in the research.

鈥淭hat鈥檚 a really big deal,鈥� he said. 鈥淚t鈥檚 an approach that is widely applicable to a lot of genes and a lot of different types of cancer. I think it鈥檚 going to be met with a great deal of enthusiasm and interest from researchers in human cancer therapy.鈥�