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Date: November 28, 1995 
Contact: Public Health Service, NCI (301) 496-6641

Reporting in the Dec. 1 Nature Medicine, the researchers said that too much expression of an important gene that regulates cell division may be involved. Overexpression of the gene is rarely seen when a breast lesion is benign, the researchers found, but it rises as these lesions move from a premalignant state to the earliest stages of cancer.

The researchers found that overexpression of messenger RNA for cyclin D -- a cell cycle protein -- increases at a discrete point in human breast cancer progression -- the boundary between two types of changes in the breast that microscopically share similar patterns, but which carry different relative risks for developing breast cancer over time.

The two types of changes are atypical ductal hyperplasia (ADH) and low-grade ductal carcinoma in situ (low-grade DCIS). Women with ADH, which is an abnormal growth of breast cells, have 4 to 5 times the chance of developing breast cancer over 15 years as women without the condition. Women with low-grade DCIS, a condition in which cancerous cells are found in the milk ducts of the breast but nowhere else, have an 8 to 10 times greater chance of developing breast cancer during this time.

"We're putting a marker on the map and saying we can see differences between these two types of changes ... between a moderate and a high risk of eventually progressing to invasive breast cancer," noted Patricia Steeg, Ph.D., chief of the Women's Cancers Section in NCI's Laboratory of Pathology and a principal investigator of the study.

A third type of breast lesion, high-grade DCIS, is more easily identified, and the development of metastatic disease is generally considered more of a certainty in women who develop this lesion, according to the researchers. But the new molecular marker may not only aid clinicians in distinguishing between ADH and low-grade DCIS, but also between low-grade and high-grade DCIS. At present, women whose biopsies reveal either of these conditions are treated surgically, either through mastectomy or lumpectomy.

"To me, what's exciting is we now have a mechanism through which we might be able to control the development of breast cancer," said David Page, M.D., director of Anatomic Pathology and Professor of Pathology at Vanderbilt University School of Medicine, Nashville, Tenn., and a co-principal investigator. "This is also an observation that can be taken into a population of women and tested."

To assess molecular alterations during human breast cancer progression, the researchers evaluated 94 biopsy lesions. Elevated levels of cyclin D mRNA were observed in 18 percent of benign breast lesions, which confer no or a slightly increased breast cancer risk, and also in 18 percent of ADH lesions. However, during the transition to the earliest forms of cancer, the researchers found a much higher level of cyclin D in 76 percent of low-grade DCIS and in 87 percent of high-grade DCIS. Moreover, in those low-grade DCIS that were presumably more apt to progress to metastases or to spread to other body sites, cyclin D levels were also high (92 percent).

This finding jibes with Page's observation that changes in breast cells may progress in a fashion similar to that seen in the cervix. In the cervix, when a carcinoma in situ is discovered, Page said, many of the abnormal cases fail to develop into invasive cancers. "And we think the same thing may be true in the breast as well." Ultimately, as additional molecular markers are discovered, he said, more conservative treatments might develop for some women with these early breast lesions.

An estimated three-quarters of a million biopsies are done each year in women with suspicious mammograms. Of these, atypical ductal hyperplasia accounts for roughly 5 percent, while ductal carcinomas in situ account for varying percentages, depending on the population of women studied.

Cyclin D belongs to the cyclin family of genes, all of which are being studied for their role in human breast cancer progression. Because there is a relative lack of cyclin D gene expression in typical hyperplasias, the researchers theorize that cyclin D is more important to the transformation of breast cells to cancer than simply to cell reproduction. Moreover, atypical hyperplasia may not actually be a direct precursor on the path to breast cancer.

"We find this tumor marker particularly interesting," said Page, "because it's involved in one of the major final steps before a cell divides."

Added Steeg, "Too much cyclin D does appear to correspond to a cell's commitment to carcinoma'." She said future studies will look at both messenger RNA and protein expression levels of each member of the cyclin gene family, as well as their potential functions.

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