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 that determining whether breast cancer patients have mutations in this gene could help tailor the most effective treatment for individual patients. Their research is reported in the May issue of Oncogene.
The malfunctioning gene, recently shown by the Duke researchers to be important in transforming normal liver cells into cancer cells, now has also been demonstrated to be defective in about 30% of cases of sporadic breast cancer. The gene, mannose 6-phosphate/insulin-like growth factor H receptor (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, professor of radiation oncology at Duke. "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."
Jirtle's coauthors on the Oncogene paper are Gerald R. Hanking, 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 Company, Zeneca Pharmaceuticals, and MITRE Corporation.
Gene Testing May Aid in Drug Selection
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."
To help sort out the roles of different genes in tumor growth, the Duke researchers focused on the M6P/IGF2r gene. Previous studies had shown 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 whether 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% 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 helps activate a potent growth inhibitor, transforming growth factor-beta-l (TGF-beta-l). High levels of TGF-beta-l help stop the growth of many tumor types.
Presence of Gene May Predict Responsiveness to Tamoxifen(Drug information on tamoxifen)
The commonly used cytostatic drug tamoxifen (Nolvadex) appears to work, in part, by prompting cells to produce larger quantities of TGF-beta-l, which is released in an inactive form. To become activated, TGF-beta-l requires the M6P/IGF2 receptor. If the M6P/IGF2 receptor is missing or inactive because of mutation, TGF-beta-l 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 two promising anticancer drugs, limonene and perillyl alcohol(Drug information on alcohol), work by increasing levels of both TGF-beta-l 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 antitumor agents as tamoxifen.
Previous studies by Jirtle's group at Duke and Michael Gould at Wisconsin have shown that, in rats, limonene caused 87% of advanced mammary tumors to shrink. However, in cells in which the levels of M6P/IGF2 receptor did not increase, suggesting that the gene is defective, limonene was also ineffective.
Gould and colleagues are now conducting phase I safety studies of perillyl alcohol in breast cancer patients and later this year plan to proceed to phase II studies that will assess its effectiveness in treating breast cancer tumors.
The Duke team will test tumor tissue from each patient to determine whether mutations in the M6P/IGF2 receptor indeed correlate with responsiveness to the drug. The study could help doctors identify which patients would be the best candidates for treatment with the new drugs, should they be approved for general use, Jirtle said.