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Release: March 15, 2000

UI researchers answering basic science questions about how breast cancer spreads

IOWA CITY, Iowa – Findings from a University of Iowa Health Care study may explain the basic mechanisms involved in triggering the spread of breast cancer.

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 silencing.

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 team.

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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