Putting the brake on cancer
Discovery of biomarkers could lead to therapies for tumor suppression
By Lindy Brounley
When a movie character says, “It’s too quiet,” that’s usually a sign something bad may happen.
Now, UF 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 the online version of Oncogene, show that drugs can potentially suppress tumor growth by restoring cellular processes rather than inhibiting cancer-causing genes known as oncogenes.
“It’s a well-accepted fact that you can inhibit things, particularly oncogenes, that drive cancer. Oncogenes are the cancer’s gas pedal,” said principal investigator David Reisman, M.D., Ph.D., a UF associate professor of medicine and a member of the UF Shands Cancer Center. “What we’ve done is demonstrate the feasibility of reconstituting the cancer brake.”
The protein, known as Brahma, or BRM, is involved in the regulation of cellular functions like gene expression, DNA repair and cell adhesion. It also has a role in telling cells whether to divide and grow or stop dividing and die. Other studies have found “silenced” BRM is present in 10 to 20 percent of all solid tumors.
Reisman knew from his own research 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.
“The 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,” 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’s work shows that two variations, or polymorphisms, within the BRM gene could be biomarkers for lung cancer and help doctors identify individuals at higher risk. This could lead to more cost-effective screening and lifesaving early detection.
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 verified the presence of the silenced BRM variants in human lung tumors.
Reisman and Lui also conducted control studies on people matched for age, gender and smoking history. Of them, 484 individuals had lung cancer and 715 were healthy and cancer-free.
“The chance that you would develop lung cancer if you had both polymorphic sites was 220 percent higher,” Reisman said.
The team also studied whether it would be possible to restore normal expression of the BRM protein. Certain compounds, called histone deacetylase — or HDAC — inhibitors, had been demonstrated by other researchers to reactivate the BRM gene, but did not restore the 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.