Decreased activity within the Transforming Growth Factor Beta (TGF-beta) pathway is associated with increased breast cancer risk, according to a study published by researchers at Northwestern Memorial Hospital and Northwestern University's Robert H. Lurie Comprehensive Cancer Center in the journal Cancer Research.

This is the first study aimed at determining whether various combinations of two naturally-occurring variants of the TGF-beta pathway may predict breast cancer risk. It is also the first study assessing a cancer-related pathway by means of two functionally-relevant variants.

Blood tests were performed on 660 patients with breast cancer and 880 healthy females for two TGF-beta variants: TGFBR1*6A and TGFB1 T29C. "Our study shows that TGFBR1*6A is associated with a 120 percent increased risk of breast cancer among women older than 50," says study author Boris Pasche, MD, PhD, FACP, director of Northwestern's Cancer Genetics Program and assistant professor of Medicine at Northwestern University's Feinberg School of Medicine.

"Importantly, the results show that women with the lowest levels of TGF-beta activity have a 69 percent higher risk of breast cancer than women with the highest levels of TGF-beta activity as predicted by the combination of the two variants TGFBR1*6A and TGFB1 T29C," says Pasche. "This finding is promising as it may eventually help us predict breast cancer risk in a large subset of the population. Indeed, breast cancer risk may be predicted in 30 percent of women through assessment of the TGFBR1*6A and TGFB1 T29C variants."

Mutated genes like TGFBR1*6A and the better-known cancer susceptibility genes BRCA1 and BRCA2, alter cells in a way that causes them either to grow faster or become cancerous. Pasche says while BRCA1 and BRCA2 genes have been implicated in an estimated 3 to 7 percent of all breast and ovarian cancer cases, studying TGFBR1*6A is important because it is a far more common gene as one in every eight individual carries at least one copy of this gene. The BRCA1 and BRCA2 genes are found only in one of every 400 to 800 people. The impact of TGFBR1*6A is shown by the fact that in 2005 more than 14,000 new cases of breast cancers in the US alone may be attributable to TGFBR1*6A.

"Most cases of breast, ovarian and colon cancers are caused by damage to the genes that builds up over a lifetime, but some people are born with a high risk of the disease," explains Pasche. "When inherited, the TGFBR1*6A gene makes people susceptible to having certain cells grow and divide uncontrollably, which may contribute to cancer development."

"In the near future, it will be commonplace for people to know what genes make them more susceptible to cancer, and we'll have many more options for preventing those cancers," says Pasche.

Virginia Kaklamani M.D., an oncologist at Northwestern Memorial Hospital and assistant professor of medicine at the Feinberg School of Medicine, is the first author of the study. She adds, "The testing of TGFBR1*6A is not ready for primetime yet. We still have to understand its role in relation with other genes that we commonly test for, such as BRCA1 and BRCA2. "However, in the foreseeable future, we may be able to identify high-risk women more precisely because of the TGFBR1*6A mutation and prevent many cases of breast cancer."

SOURCES:
Cancer Research, April 15, 2005
Northwestern Memorial Hospital (http://www.nmh.org)