A woman's risk of developing breast cancer is due in part to a group of very small variations in genes which code for a cell's estrogen receptors, according to a collaborative study by scientists at the National Cancer Institute (NCI), part of the National Institutes of Health, Memorial Sloan-Kettering Cancer Center, Celera Diagnostics, SAIC-Frederick Inc., Applied Biosystems, the Massachusetts Institute of Technology and Vanderbilt University School of Medicine. The study appears in the December 15, 2004, issue of "Cancer Research".

Many breast cancers depend on estrogen and progesterone to grow. Cells in these cancers have proteins called estrogen and progesterone receptors on their surface. Receptors are an outside molecule's gateway to the cell: molecules bind to and sometimes pass through receptors into the cell. In breast cancers dependent on these two steroid hormones to grow, estrogen and progesterone bind to their respective receptors, initiating signalling pathways that cause the cancer cells to multiply.

Researchers led by Bert Gold, Ph.D., a scientist in NCI's Center for Cancer Research, studied the association between breast cancer risk and very small differences in the genes coding for estrogen and progesterone receptors. Called "single nucleotide polymorphisms," these versions of the gene differ by a single nucleotide -- the molecular subunit of DNA. Though these differences are small, they can have an impact on how an estrogen receptor performs.

NCI scientists examined connections between an estrogen receptor gene, called "ESR1," and breast cancer. Of 17 single nucleotide polymorphisms (variations) of "ESR1" under study, there were two polymorphisms associated with breast cancer susceptibility. One was associated with disease only in women over 50; additionally, this polymorphism was very rare in the African-American population. The other polymorphism was associated with disease only in Ashkenazi (Central or Eastern European) Jewish women over 50.

The researchers found that a group of single nucleotide polymorphisms in the third most common "ESR2" gene in Ashkenazi women under study was associated with breast cancer susceptibility. This is one of the first studies to examine breast cancer susceptibility and "ESR2" polymorphisms since the discovery of "ESR2" in 1996. They studied eight other polymorphisms in "ESR2" and found no groups of polymorphisms associated with disease in the general population.

Gold and his colleagues also found no association between breast cancer and 13 single nucleotide polymorphisms in the progesterone receptor gene.

The study population included DNA samples from 1,006 women with breast
cancer (identities were masked) who were patients at Memorial Sloan-Kettering in New York City and 613 control subjects from 14 sites that are part of the New York Cancer Study. The two groups had similar proportions of women over and under 50 and of women who had menopause before or after age 50. Case and control groups also contained similar proportions of women in six ethnic groups: those of European, African, Asian, Hispanic, Ashkenazi, and unknown descent.

There is good news for some women. "We were pleasantly surprised to discover that some women have some genetic protection from breast cancer," said Gold.

Three groups of single nucleotide polymorphisms in the "ESR1" gene protected against the risk of the disease across the ethnic and age groups. However, only one of these was protective when NCI scientists examined only European-Americans.

"We know that half of familial breast cancer is due to genetic factors other than 'BRCA1' and 'BRCA2,'" said Kenneth Offit, M.D., a cancer geneticist at Memorial Sloan-Kettering and a co-author of the study. "These findings
suggest that genetic variants in estrogen receptor pathways may be one of many such risk factors."

"Hormone receptors are also the target of several anticancer drugs," said Michael Dean, Ph.D., NCI, another co-author of the report. "We hope pharmaceutical developers will take our results into account as they develop new drugs that modulate the effects of estrogen on breast cancer cells."