New Class of Genes Play a Role in Breast Cancer Risk

Newswise — A University of Massachusetts Amherst researcher has identified a new class of genes that appear to play a significant role in breast cancer risk. The results have been published online in The American Journal of Pathology.

Joseph Jerry, veterinary and animal sciences, has identified genes that appear to modify the action of mutations in a tumor suppressor gene called p53 and explain why identical mutations in this gene don't always result in breast cancer. P53 is one of several genes that produce proteins that act to suppress the formation of tumors. Mutated copies of the gene stop producing active proteins and increase a carrier's risk of developing the disease.

Together with post-doctoral researchers Anneke Blackburn and Linda Hill, Jerry has identified a gene that appears to compensate for missing proteins from genes like p53 when functioning correctly and explains why some people with p53 mutations do not develop breast cancer. Jerry also found that mutant variants of this gene can increase the risk of developing breast cancer in mice with p53 mutations. Most research on the genetic causes of breast cancer has focused on the action of a handful of high risk mutations or variants like p53 and BRCA1 that greatly increase a carrier's chance of developing the disease, but these account for a small number of genetically based breast cancers. In addition, identical mutations don't always cause the disease. The search for additional high risk variants to explain these trends has proved fruitless, stimulating interest in variants with smaller effects. "The research community is becoming increasingly aware that there may be variants of 13 to 18 genes present within the population and that each contributes a small increase in risk," says Jerry. These variants were the target of Jerry's research.

Using mice as a model for breast cancer, Jerry focused on two strains of mice that had identical mutations in p53 but differed in their susceptibility to mammary cancer. These strains of mice were crossed, and after 18 months some of the mice developed mammary tumors and others didn't. DNA from the group that developed tumors was compared to the DNA from the non-tumor group. Jerry found a section of DNA that was different in the two groups.

Jerry hypothesized that there should be a gene on this section that was working in the healthy mice and deficient in the tumor group. He looked at each of the genes on this section of chromosome to see if the products they made occurred at different levels in the mouse tissue, ruling out nearly 300 other candidates before identifying DMBT1 as the gene whose products were missing or occurred at lower levels in the tumor group. The lack of these products is associated with increased cancer risk in p53 deficient mice, while a functioning DMBT1 gene seemed to provide protection against cancer.

Jerry and Baystate Medical Center pathologists Jackie Cao and Christopher Otis then sought to determine if low levels of the proteins produced by DMBT1 was a characteristic of human breast cancer. Their findings in human tissue demonstrated that women with breast cancer had lower levels of the proteins made by DMBT1 than women without cancer.

According to Jerry, the next step is to focus on the function of DMBT1 and determine how it affects cancer risk. Knowing how DMBT1 influences risk may lead to interventions that take a woman who is very susceptible to breast cancer and make her more resistant. "Once you know the mechanism, you can develop drugs to target this gene or pathway," says Jerry.

"DMBT1 is also relevant to diagnostics and prognosis," says Jerry. Accounting for the action of genes will allow for an accurate assessment of a woman's risk of breast cancer and provide more appropriate treatment. If a woman has a bad copy of a gene like p53 associated with a high risk of breast cancer but has a functioning DMBT1 gene, then her prognosis is likely to be better than a woman with mutations in both genes.