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
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
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, 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