Inherited Factors Play an Important
Role in Breast Cancer Progression According to New Study in
New research in mice and five independent collections of human
breast tumors has enabled National Cancer Institute (NCI) scientists
to confirm that genes for factors contributing to susceptibility
for breast cancer metastasis can be inherited. The new findings
support earlier results from the same laboratory and appear in
the Jan. 1, 2009, issue of Cancer Research.
The study results also show that gene activities in tumor cells
and immune cells that infiltrate, or invade, tumors can contribute
to the development of expression profiles, called gene signatures,
that are predictive of cancer progression. The analysis of normal
mouse tissue as well as tumors transplanted into mice suggests
that predictive, or prognostic, gene signatures that point to a
tumorís potential for spreading throughout the body can be the
result of both inherited and non-inherited factors, with inherited
factors being more consistently predictive. The research team that
reported these findings is from the Center for Cancer Research
at NCI, which is part of the National Institutes of Health.
The researchers were able to perform their analyses by using advances
in microarray technology, which allows scientists to scan vast
amounts of genetic information and identify gene signatures that
can be used to predict cancer outcomes. Many scientists had assumed
that metastatic ability is primarily determined by somatic, or
non-inherited, gene mutations in tumor tissue. "Our earlier
studies clearly established that inherited factors also play an
important role in metastatic progression and can help distinguish
which tumors have a propensity to metastasize," said author
Kent W. Hunter, Ph.D., head of NCIís Metastasis Susceptibility
Section in the Laboratory of Cancer Biology and Genetics. "Hopefully
in the future we will be able to determine which women are more
likely to have a tumor that would metastasize, and we could then
tailor therapy specifically for them, avoiding the use of harsh
treatments for those with a low probability of metastasis."
To determine whether mouse tumor gene expression profiles could
be used to predict outcomes in human breast cancer, the investigators
identified a gene expression signature that allowed them to distinguish
between the tumors of mice that have a high or a low inherited
susceptibility to tumor metastasis (a 20-fold difference). They
then converted the mouse gene signature to the corresponding human
gene signature and analyzed five pre-existing sets of human breast
tumors. This signature successfully predicted outcomes (either
relapse or disease-free survival) in four of the five sets of human
Because other studies have suggested that gene expression patterns
in the nearby tissue, or stroma, are altered in tumors that are
prone to metastasis, the investigators conducted transplant experiments
by putting highly metastatic tumor cells into the mammary fat pads
of mice that have either a high or a low susceptibility to tumor
metastasis. These transplants resulted in tumors that had identical
tumor cells but different stroma and immune cells that infiltrated
the tumor. No significant differences were seen in tumor weight
or metastasis to the lung in the two types of mice after 28 days,
suggesting that metastatic differences between individual mice
in this experiment were possibly due to genes in the outer layer
of tissue that surrounds the tumor (the epithelium) rather than
in the stroma. However, differences in gene signatures were still
seen in mice with either high or low potential to develop metastases,
and the corresponding human gene signatures were predictive of
relapse or survival in patients. The researchers concluded that
both the tumor epithelium and the stroma probably contributed to
the development of the prognostic gene profiles.
"Our study provides additional evidence of the role of inherited
genes in human breast cancer progression. Therefore our next step
is to improve our current understanding of the role of the epithelium
and stroma in tumor progression and develop more effective therapeutic
strategies based on our new knowledge," said Hunter.
For more information on Dr. Hunterís research, please go to http://ccr.cancer.gov/staff/staff.asp?profileid=13660.
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and their families, through research into prevention and cancer
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Reference: Lukes L, Crawford NPS, Walker R, and
Hunter KW. The origins of breast cancer prognostic gene expression
profiles. Cancer Research. January 1, 2009. Vol. 69, No.