Researchers at The University of Texas M. D. Anderson Cancer Center now have evidence that receptors found on tumors that were believed to function only on the surface of cells can actually switch on genes inside a cell's nucleus, thus promoting cancer development in two distinct ways.
They specifically found that HER-2 cell surface receptors, known to promote breast and other cancers when they allow too many growth signals to enter a cell, can actually travel into the nucleus and turn on a variety of genes, including COX-2, which also is associated with carcinogenesis.
The discovery, published in the September issue of the journal Cancer Cell, likely will revolutionize the way scientists think about membrane receptors, says the study's lead author, Mien-Chie Hung, Ph.D., a professor in the Department of Molecular & Cellular Oncology.
"For a number of years, researchers have found membrane receptors associated with cancer development in the nucleus of cells, but they believed these were just debris left over from the receptor's primary job, which is to shuttle signals into a cell," says Hung.
"Here we find that a receptor protein known to be important in one cancer pathway also can enter a cell's nucleus to turn on genes associated with a different carcinogenesis pathway," he says. "Proof of the dual nature of these receptors may well change the nature of research associated with them and, possibly, treatment strategy."
The team of researchers revealed the double-dealing nature of the HER-2 protein receptor after they developed a new cloning and bioinformatics technique to track the path of the receptor. This technology, they say, can now be used by scientists to look for duplicitous behavior in other cell surface proteins.
They developed a method to remove the membrane and outer portion of a cancer cell so that little more than the nucleus was left, and then used an antibody that attached to the HER-2 protein to detect what the receptor protein was doing. They found that HER-2 did attach to a number of genes in the nucleus, one of which is the "promoter" region of the cyclooxygenase-2 (COX-2). In other words, HER-2 was activating the transcription of COX-2.
"Each works in a completely different way, and no one thought that one could be regulating the other," Hung says.