GAITHERSBURG, MarylandResearchers have identified 18 genes that
behave similarly to estrogen-receptor-alpha (ESR1) in patients with
estrogen-receptor-positive (ER-positive) breast cancer. The cluster includes
seven genes not previously associated with estrogen regulation or with breast
cancer, Mihael H. Polymeropoulos, MD, head of pharmacogenetics, Novartis
Pharmaceuticals Corporation, told ONI in an interview.
Dr. Polymeropoulos and his colleagues described the cluster in an article in
The Pharmacogenomics Journal (1:135-141, 2001). He said that some activity in
the cluster might be coincidental to breast cancer, but all 18 genes should be
investigated as potential biomarkers for predicting how individual patients
will respond to endocrine therapies such as tamoxifen (Taxol) and letrozole (Femara). "This is the beginning of customizing the treatment of breast
cancer," he told ONI.
ER-positive breast cancers are less likely to relapse and have better
overall survival rates, he said, but about half do not respond to antiestrogens
or estrogen-deprivation therapy. The hope is that supplementing ESR1 with
additional markers will help physicians differentiate tumors by their genetic
fingerprints and choose treatments accordingly.
The following seven genes had not previously been linked to estrogen
stimulation or breast cancer: SCNNIA, SERPINA3, ASAH, LCN1, TGFBR3, GRIA2, and
CYP2B. The other genes in the cluster are: CEACAM5, MGB1, LIV-1, PIP, MGP,
TFF1, TFF3, HNF3A, HPN, XBP1, and AZGP1.
Dr. Polymeropoulos’ group found the genes via a DNA microarray, which can
analyze gene expression at the level of RNA. In this process, he said, small
glass slides containing minute amounts of thousands of known genes are matched
against each biopsy sample. The gene "chips" on each slide can
rapidly detect which of the thousands of genes are expressed in a human tissue
In this study, the investigators examined gene expression for 7,000 genes in
RNA taken from 53 breast tumors and from six other samples, including pooled
normal breast tissue. That was as many genes as could be studied at the time,
but Dr. Polymerop-oulos predicts that all 30,000 or more genes in the human
genome will eventually be screened for overexpression in ER-positive breast
Twenty-one RNA samples in the study came from a randomized phase III
clinical trial of letrozole vs tamoxifen that led to the FDA’s approval in
January 2001 of letrozole tablets as a first-line hormonal treatment for
advanced breast cancer in postmenopausal women.