Double Dealing Receptor Protein On Tumors Promotes Cancer Development In Cell Nucleus

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.

Up to 30 percent of breast cancers "over-express" the HER-2 cell surface protein, which pushes the cell to grow. Over-expression of COX-2 does not allow a damaged cell to die and also is associated with cancer cell invasion and metastasis, he says.

Both also are targets for cancer treatments: the breast cancer drug Herceptin has proven beneficial in delaying progression in women whose tumors are HER-2 positive, and the use of non-steroidal anti-inflammatory drugs (NSAID), which slows down expression of COX-2 is being tested as a chemopreventive agent in people who are at high risk of developing certain cancers.

Hung says now that the technology has been developed, researchers can track a variety of membrane receptor tyrosine kinases that have been found inside the nucleus, many of them regulate a variety of cell functions, including proliferation, differentiation and survival. These include other epidermal growth factor receptors (EGFR), of which HER-2 is a member, the vascular epithelial growth factor (VEGF) receptors known to stimulate tumor angiogenesis, and insulin receptors, among many others.

"Science is based on available technology," he says. "And now we can have a peephole into the nucleus that I believe will open up whole new avenues of research."

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The study was funded by National Institutes of Health grants, the National Breast Cancer Foundation, the Susan G. Komen Breast Cancer Foundation, and a National Institutes of Health postdoctoral fellowship. Co-authors include Shao-Chun Wang, Ph.D., Huang-Chun Lien, M.D., Weiya Xia, M.D., I-Fen Chen, Ph.D., Hui-Wen Lo, Ph.D., Zhiqin Wang, M.S., Mohamed Ali-Seyed, Ph.D., Dung-Fang Lee, M.S., Geoffrey Bartholomeusz, Ph.D., Fu Ou-Yang, M.D. and Dipak K. Giri, Ph.D. All of the authors are associated with the Department of Molecular & Cellular Oncology except for Huang-Chun Lei, who is now at National Taiwan University Hospital in Taiwan.