Discovery suggests location of genes for breast density, a strong risk factor for breast cancer

Studying the DNA of 889 people, gene hunters at the Mayo Clinic and H. Lee Moffitt Cancer Centers have identified a region on chromosome 5p that is significantly associated with dense breast tissue, a known risk factor for breast cancer. The findings, published in the September 1 issue of Cancer Research, a publication of the American Association for Cancer Research, suggest that genes which influence breast density could serve as a predictive marker for disease and provide a biological target for agents that may reduce breast cancer risk by reducing breast density.

Women with dense breasts – meaning the breast has a smaller proportion of fat relative to stromal and epithelial tissues − are three to five times more likely to develop breast cancer than women with less dense breasts, according to the researchers.

Scientists have estimated the total influence of genes on breast density to be about 60 percent.

The study, the first reported genetic linkage analysis for genes influencing breast density, “provides further evidence that this trait does appear to be genetically influenced,” said the study’s lead investigator, Celine Vachon, Ph.D., an epidemiologist at the Mayo Clinic in Rochester, Minnesota.

Although the investigators have strong evidence that a gene residing in this chromosomal region influences breast density, the exact gene that is responsible is not yet known. “One or more of the 45 candidate genes in this region could explain a large proportion of mammographic breast density, and potentially, breast cancer,” she said.

Within the region on chromosome 5p, the gene which encodes the prolactin receptor in particular, stands out as a possible contributor to dense breasts. Prolactin is a hormone that helps enlarge mammary glands during pregnancy and, after childbirth, is involved in milk production. Previous research has found a correlation between mammographic density and prolactin levels in postmenopausal women, the researchers note.

Vachon’s team took what they term an “agnostic” approach to uncovering genes, or gene regulators like microRNA, that are involved in the development of dense breasts. “We assume we don’t know anything about the biology of the trait and we let the genomes of our participants and their breast densities guide us,” Vachon said.

Their method contrasts the traditional “candidate gene” approach, where scientists look at variations in specific genes thought to be involved with the disease or trait of interest. Such linkage studies have been used to uncover many high-impact risk genes, such as the breast cancer susceptibility genes BRCA1 and BRCA2.

The Mayo researchers performed a genome-wide linkage scan to identify possible chromosome regions in 89 families, part of a multi-generational Minnesota family study that began in 1944 at the University of Minnesota. Blood samples and mammograms were collected and analyzed for 756 female participants; 133 men were also included to help clarify genetic information in their offspring, mothers and sisters. “We used the relationship between family members and breast density to inform where a gene might be,” Vachon says.