Researchers have discovered five risk variants for breast cancer that lie in the vicinity of the gene that codes for the estrogen receptor. Four of the variants occur within enhancer regions and reduce expression of the receptor, and the fifth is in a silencer region and increases expression.

Researchers have discovered five common genetic variants that may increase breast cancer risk by altering estrogen-receptor (ER) expression.

Whether a breast tumor expresses the ER is one of the key criteria for identifying the cancer's subtype and selecting treatment. The 80% of breast cancers that are ER-positive, for example, often respond to drugs such as the selective estrogen receptor modulator tamoxifen. Although genome-wide association studies (GWAS) suggest that SNPs in the vicinity of ESR1, the gene that encodes the ER, increase the likelihood of developing breast cancer, researchers hadn't been able to pin down which variants are responsible.

A team of more than 200 researchers, led by scientists at the University of Cambridge in the United Kingdom and the QIMR Berghofer Medical Research Institute in Australia, combined genomic data on 118,816 women from more than 100 studies. About half of the women had breast cancer, and the others were controls.

After analyzing 3,872 SNPs across the region that includes ESR1, the team found evidence for five variants in or near the gene that directly contribute to breast cancer risk. Four of the five variants occurred in enhancer regions and correlated with a higher risk of developing ER-negative tumors. The fifth variant, located in a silencer region, correlated with increased odds of developing ER-positive disease.

To determine how the variants affect ESR1 expression, the researchers modified breast cancer cell lines to carry each of them. Those experiments suggested that the four variants implicated in ER-negative tumors reduced ESR1 expression, whereas the fifth increased ESR1 expression, the scientists reported.

“These genetic variants that alter risk appear to act by changing the amount of estrogen receptor that's being made in the cell,” says co-author Alison Dunning, PhD, of the University of Cambridge. “It looks like there's a Goldilocks zone” of ideal estrogen receptor expression that is optimal for the cell, she says, whereas higher or lower levels may promote cancer.

Dunning says that none of the five variants has substantial impact on breast cancer risk. She and her colleagues are working to create a composite profile that could be useful for predicting risk, which would include the five new variants and about 500 others that were previously discovered.

Sara Lindström, PhD, of the University of Washington in Seattle, who wasn't connected to the study, praises the research for using several approaches to identify the variants and probe their effects. “It shows how we can follow up on GWAS hits.” She says researchers now need to confirm that these variants promote breast cancer and, if so, determine how. –Mitch Leslie