CONTACT: JENNIFER CRONIN
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Iowa City IA 52242
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Release: March 15, 2000
UI researchers answering basic science questions about how breast cancer
IOWA CITY, Iowa Findings from a University of Iowa Health Care study
may explain the basic mechanisms involved in triggering the spread of breast
In an article appearing in the March issue of the International Journal of
Cancer, UI researchers show that processes known as aberrant cytosine methylation
along with chromatin condensation may "turn off" or silence maspin
(mammary serine protease inhibitor). Maspin is a gene that is normally expressed
in healthy mammary cells and suppresses the development and spread of tumors.
When the maspin gene becomes silenced, tumors can grow and spread.
Although these basic science findings will not be translated into clinically
applicable therapies for several years, uncovering some of the molecular mechanisms
underlying factors that silence maspin is a promising step forward in eventually
developing possible ways to treat the often deadly condition.
"DNA methylation is mediated by enzymes, and generally any process mediated
by enzymes can often be affected by pharmacological interventions," said
Frederick Domann, Ph.D., UI associate professor of radiology.
Researchers have been focusing on tumor suppressor genes in an effort to
figure out how cancer grows and spreads. Classical genetics has shown that
mutations and deletions of tumor suppressor genes contribute to malignancy.
However, in the case of maspin and some other tumor suppressors, the gene
is not rearranged or deleted, which has prompted Domann and other investigators
to consider cytosine methylation and related processes as mechanisms of gene
Methylation is the addition of single carbon atoms to specific target sites
within DNA. Cytosine, one of the four nucleotides in DNA, is the only base
that can be methylated. Cytosine is normally methylated in cells at certain
positions and not others. However, carcinogenesis alters the pattern of cytosine
methylation, which contributes to altered patterns of gene expression in cancer.
Chromatin condensation, the second process affecting breast cancer, involves
chromatin, the genetic material found in the nucleus of cells. During chromatin
condensation or heterochromatization, the chromatin becomes condensed and
inaccessible to proteins required for efficient gene expression.
To test their hypothesis about the underlying reasons for silencing maspin
expression, the UI researchers compared cultured normal human mammary epithelial
cells (HMEC) to nine cultured human breast cancer cell lines. The UI team
received these samples from colleagues at the University of Arizona.
The researchers found that maspin gene promoters within the normal cells
were not methylated. In seven of the nine breast cancer cell lines, there
was no detectable maspin expression, and six of these seven maspin-negative
breast cancer cell lines also had an aberrant pattern of cytosine methylation
of the maspin promoter.
"These new findings provide critical information regarding the regulatory
mechanisms of maspin, which allows us to examine the potential of maspin re-expression
in cancer therapies," said Mary J.C. Hendrix, Ph.D., UI professor and
head of anatomy and cell biology, associate director of basic research and
deputy director of the UI Cancer Center, and a member of the maspin investigative
Hendrix, along with researchers at the Dana Farber Cancer Institute and Harvard
Medical Center, were the first to report the discovery of maspin and its ability
to slow the growth and spread of breast tumors in 1994. Hendrix recently contributed
an invited commentary on the status of maspin research, which will appear
in Nature Medicine in late March.
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