New predictive marker found for prostate and colon cancer

August 02, 2002

ANN ARBOR, MI - A protein that interacts with the gene for Huntington's disease could also help physicians diagnose and more effectively treat patients with two of the most common and deadly forms of cancer, according to a new University of Michigan study.

Absent in normal prostate and colon epithelial cells, but found in large amounts in prostate, colon and other tumor cells, it is called huntingtin interacting protein or HIP1. The protein has never before been associated with any type of cancer. (Editors: Note "huntingtin" is correct spelling.)

"Anytime you find a true marker for cancer, it's surprising," says Theodora S. Ross, M.D., Ph.D., an oncologist in the U-M's Comprehensive Cancer Center and an assistant professor of internal medicine in the U-M Medical School. "But HIP1 also is unusual, because it seems to be such a strong prognosticator, especially for prostate cancer."

Results of U-M research on HIP1's relationship to human prostate and colon cancer were published August 1 in the Journal of Clinical Investigation.

"We don't find significant HIP1 expression in normal prostate epithelial cells, but as prostate cancer develops and progresses, we see a steady increase in HIP1 expression," Ross explains. "HIP1 was expressed in 50 percent of tumors from patients in the earliest stages of cancer, 88 percent of tumors from patients with localized prostate cancer, and 100 percent of patients with metastatic prostate cancer."

"High levels of HIP1 were present in every stage of colon cancer," Ross adds. "In melanoma, breast and ovarian cancers, the expression patterns varied, but HIP1 was consistently over-expressed."

During her post-doctoral fellowship at Boston's Dana-Farber Cancer Institute, Ross cloned the protein from bone marrow cells of a patient with leukemia. Since joining the U-M Medical School three years ago, she has focused on nothing but HIP1 and its relationship to an important cellular trafficking and signaling system called the clathrin-mediated trafficking pathway. Cells use this system to remove old receptors and signaling molecules on cell surfaces and replace them with new molecules.

The HIP1 protein appears to be involved in this process, according to Ross, along with another protein called htt, which is expressed by the mutated gene responsible for Huntington's disease - an inherited, progressive form of dementia. Although both proteins are found in parts of the cell where movement of material occurs, their exact role is unknown. The connection to the Huntington's gene could be significant, however, "because people with Huntington's rarely get cancer," Ross adds.

"This is a new pathway in tumorigenesis; no one else is working with it in this context," Ross says. "Our paper is the first demonstration of a connection between tumor formation and a protein involved in this cell trafficking pathway."

Ross' laboratory is now trying to understand the relationship between HIP1 and cancer cells. "Originally, I thought HIP1 was a tumor suppressor gene, but it could be a survival factor that prevents cancerous cells from dying or an oncogene causing normal cells to become cancerous. It could have varying effects, depending on the cell or tissue type. More research is needed to know for sure," she says.

Results included in the JCI paper showed that when U-M researchers created a mutant version of HIP1 by knocking off one segment of the protein, the result was massive cell death. "When we made a mutant that interfered with the function of the normal protein, the cells died, which suggests that HIP1 is necessary for cell survival," she says.

If scientists can discover the functional relationship between HIP1 and cancer, Ross believes it should be possible to develop agents that could kill prostate and colon tumor cells without harming the normal epithelial cells lining the inside of these organs.

In her study, Ross first measured levels of HIP1 expression in 60 cancer cell lines and a tissue microarray of primary tumors from the National Cancer Institute, which included hundreds of tissue samples from colon, breast, melanoma, ovarian, prostate, kidney and lung cancer. "We never could have looked at all these different tumors without the NCI microarray; it's an amazing resource for investigators," Ross says.

To quantify HIP1 expression in different stages of prostate cancer, U-M researchers used tissue samples from the U-M Prostate Specialized Program of Research Excellence (SPORE) tumor bank, funded by the National Cancer Institute.

Tissue samples of various stages of colon cancer were provided and interpreted by Peter C. Lucas, M.D., Ph.D., U-M lecturer in pathology.

Research on the genetic and molecular profile of prostate cancer is part of a major initiative underway in the U-M Comprehensive Cancer Center. Its goal is to link molecular genetics and proteomics with clinical outcome for all types of cancer.

The research study was funded by the Huntington's Disease Society of America, the National Institute of General Medical Sciences and the Cancer Research Fund of the Damon Runyon Foundation.

Dinesh S. Rao, Ph.D., a U-M post-doctoral fellow, is first author of the study. In addition to Lucas, other U-M Medical School collaborators include Martin G. Sanda, M.D., associate professor of surgery and of internal medicine; Mark A. Rubin, M.D., associate professor of pathology and surgery; Ikuko F. Mizukami, Ph.D., research associate; and graduate students Teresa S. Hyun and Priti D. Kumar.

University of Michigan Health System

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