News Release

Jefferson Scientists Find Further Proof Of Damage To The FHIT Gene In Breast Cancers

Peer-Reviewed Publication

Thomas Jefferson University

Scientists at Thomas Jefferson University in Philadelphia, the University Hospital of Iceland in Reykjavik, and the National Human Genome Research Institute in Bethesda have found further evidence linking damage to the tumor suppressor gene FHIT to the development of breast cancer.

In a study of 92 Icelandic women, the researchers, led by Kay Huebner, Ph.D., professor of microbiology and immunology at Jefferson Medical College and a member of Jefferson's Kimmel Cancer Center, showed reduced levels of Fhit, the protein for which FHIT encodes, both in women with sporadic breast cancer and those with hereditary breast cancer who carry a BRCA2 mutation, a gene predisposing them to develop the disease. Among the 58 sporadic and 34 BRCA2-associated breast cancers, Dr. Huebner's team reports a "significant association" between damage to the FHIT gene at its most fragile area and a reduced expression of the Fhit protein.

She reports her team's work April 13 at the American Association for Cancer Research meeting in Philadelphia.

"Genetic alterations at this most common fragile site in the FHIT gene lead to reduced Fhit protein expression in sporadic cancers and in a much larger fraction of BRCA2-associated familial cancer," Dr. Huebner explains. "This is consistent with the idea that loss of BRCA2 function affects the stability of the FHIT site."

An improved understanding of the FHIT gene may lead to the identification of individuals predisposed to some of the most common human cancers, the development of new drugs that may arrest the growth of cancer cells, and prevention of some of the most common cancers.

In 1996, Dr. Huebner and Carlo M. Croce, M.D., director of the Kimmel Cancer Center, and professor and chair of microbiology and immunology at Jefferson Medical College, identified and characterized FHIT . The investigators found that the FHIT gene is located in the human genome's most fragile area, on human chromosome 3 in a region known as 3p14.2. The area is likely to have DNA gaps, breaks, and rearrangements. They have been working to find out if FHIT's fragility is involved in the start or progression of cancers. They believe the gene plays a role in a number of cancers, such as esophageal, gastric, kidney, breast and lung.

"We knew this [FHIT] site was prone to damage by carcinogens," Dr. Huebner says, though "we don't know what those carcinogens are or what causes the genetic breakage. In sporadic tumors, the FHIT site is damaged, and the BRCA2 gene, and maybe BRCA1, are active and can probably repair the damage. But when BRCA2 is missing, without its repair mechanism, many cells cannot repair the damage, contributing to cancer growth. Perhaps part of what BRCA2 does is to protect the integrity of the cell, especially in fragile regions.

"This [finding] shows that DNA breakage in this FHIT region leads to alterations in the Fhit protein, which seems obvious but hadn't been proved for breast cancer. The other important point is that BRCA2 function appears to be important to the stability of this genetic location.

"One of the reasons this is exciting is because of what this tells us about repair genes in general in cancer," she says. Maybe FHIT and the fragile chromosome 3 site are also more likely to be severely damaged in tumors of people with MSH2 and MLH1 such as are found in colorectal cancers. Previous studies of patients from Iceland showed a loss of DNA that was significantly higher in this region in familial compared to sporadic tumors. In this study, tumors in 31 or 37 women with hereditary breast cancer showed variously lower amounts of Fhit. All of the women had a defective BRCA2 gene predisposing them to cancer. Dr. Huebner and the research team members think that the frequency of women with a damaged FHIT in cancer cells could indicate that those with a missing BRCA2 can't repair DNA damage that occurs in FHIT. "One should look at other fragile sites in BRCA2 and BRCA1 cases and probably in MLH1- and MSH2-associated tumors, which are deficient in DNA repair mechanisms. Scientists would like to know what genes are affected by losing BRCA2 repair function. "We are trying to design experiments to see if other genetic locations are involved in chromosomal fragility in BRCA2-associated tumors."

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