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New Cancer Gene Marker Could Aid Breast Cancer Treatment

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Duke Health News 919-660-1306

DURHAM, N.C. -- Researchers at Duke University Comprehensive Cancer Center have found that a newly identified liver cancer gene is also defective in more aggressive breast tumors that may not respond to certain common types of chemotherapy.

The researchers say identifying whether breast cancer patients have mutations in this gene could help tailor the most effective treatment for each individual patient. Their research is reported in the May issue of the journal Oncogene.

The malfunctioning gene, recently shown by the Duke researchers to be important in transforming normal liver cells into cancer cells, now has been demonstrated to be defective in about 30 percent of sporadic breast cancer cases as well. The gene, called M6P/IGF2r, codes for a protein that normally helps control cell growth -- a so-called tumor suppressor.

"This study provides a first step in what we believe will be the future of breast cancer treatment: customizing therapy to each individual case," said Randy Jirtle, Duke professor of radiation oncology. "People tend to think of breast cancer as a single disease, but in reality there are many independent events in the cell that can lead to uncontrolled growth. We are beginning to learn now that one size doesn't fit all in cancer treatment."

In addition to Jirtle, authors of the Oncogene paper are Gerald R. Hankins, Rex Bentley, Mihir Patel, Jeffery Marks and James D. Iglehart of Duke; and Angus De Souza of Zeneca Pharmaceuticals, Cheshire, England. The research was supported by grants from the National Cancer Institute, The Proctor and Gamble Co., Zeneca Pharmaceuticals, and MITRE Corp.

As researchers have learned more about what causes a cell to become cancerous, they have begun to realize that treatments that work for some tumors involving gene mutations are useless for others.

"Just as doctors routinely use diagnostic tests to choose the most effective antibiotic to fight a specific type of bacterial infection, we are beginning to determine which chemotherapy drugs are effective against specific types of tumors," Jirtle said. "Our results suggest testing for this new gene may help doctors decide which treatment will work best in individual cases."

Doctors commonly use two broad classes of chemotherapy drugs to treat cancer: cytotoxic agents, which kill all actively growing cells in the body, and cytostatic agents, which induce tumor cells to self destruct.

To help sort out the roles of different genes in tumor growth, the Duke researchers studied the role of a gene called mannose 6-phosphate/insulin-like growth factor II receptor (M6P/IGF2r), which normally helps control cell growth and suppress tumor formation. Previous studies by the Duke researchers in liver tumors showed that M6P/IGF2r is often mutated in early-stage liver tumors, demonstrating that it plays an important role in the initial progression of liver cancer.

To determine if the M6P/IGF2r gene also plays a role in breast cancer, the researchers studied tissue from breast tumors of 62 patients. Normally, people have two copies of the gene. Even if one copy of the gene has a mutation, the other good copy can compensate. But when the good copy becomes deleted through a second mutation, the protein's tumor-fighting ability is lost completely. The Duke researchers showed that in 30 percent of breast cancers studied, this tumor-fighting gene was lost.

The M6P/IGF2 protein is present in all cells of the body, where it performs several important functions that control cell growth, Jirtle said. It deactivates a potent growth promoter and it helps to activate a potent growth inhibitor called transforming growth factor beta1 (TGF_1). Research has shown that high levels of TGF_1 help stop growth of many tumor types.

The commonly-used cytostatic drug tamoxifen appears to work, in part, by prompting cells to produce larger quantities of TGF_1, which is released in an inactive form. To become activated, TGF_1 requires the M6P/IGF2 receptor. If the M6P/IGF2 receptor is missing or inactive because of mutation, TGF_1 can't do its job.

"Many times it is difficult to discern which patients will respond to tamoxifen treatment," Jirtle said. "This research suggests that if the M6P/IGF2 receptor is inactivated, cytostatic drugs such as tamoxifen may not be as effective."

Similar studies conducted by Jirtle and colleagues at the University of Wisconsin, Madison, have shown that promising anticancer drugs called limonene and perillyl alcohol work by increasing levels of both TGF_1 and the M6P/IGF2 receptor. Limonene is a component of citrus fruit peel, and perillyl alcohol is a lavender extract. They belong to the same broad class of anti-tumor agents as tamoxifen.

Previous studies by Jirtle's group at Duke and Michael Gould at Wisconsin have shown that in rats, limonene caused 87 percent of advanced mammary tumors to shrink. However, in cells in which the levels of M6P/IGF2 receptor did not increase, suggesting the gene is defective, the drug was also ineffective.

Gould and colleagues are now conducting Phase I safety studies of perillyl alcohol in breast cancer patients and plan to proceed in the fall to Phase II studies that will assess its effectiveness in treating breast cancer tumors.

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