Small Variations in Genes Can Determine Risk of Developing Breast Cancer
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 signaling 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
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
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."
For more information about cancer, visit the NCI Web site at
http://www.cancer.gov or call
NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).
* Gold B, Kalush F, Bergeron J, Scott
K, Mitra K, Wilson K, Ellis N, Huang H, Chen M, Lippert R, Halldorsson
BV, Woodworth B, White T, Clark AG, Parl FF, Broder S, Dean M, and
Offit K. Estrogen receptor genes and haplotypes associated with breast
cancer risk. Cancer Research, 64. Dec. 15, 2004.