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Mutation associated with decreased breast cancer risk for
women under 50
By Lone Frank

A small variation in the construction of a woman's receptors for the hormone progesterone can have a large impact on her risk for breast cancer. A new German study shows that carriers of a well-known genetic variation have a significantly lower risk of developing breast cancer before the age of 50.

‘There is not yet a reason for women to seek genetic testing for the PROGINS variant.’

Embedded in the membrane of cells in the breast and other tissues, the human progesterone receptor, HPR, which is activated by progesterone, exists in several alternative forms. The so-called PROGINS variation has long interested scientists, but studies with small numbers of patients have turned up contradictory results. "We hoped to clear up the inconsistencies with a large epidemiological study," says epidemiologist Jenny Chang-Claude of Deutsches Krebsforschungszentrum, Heidelberg, Germany, who led the recent investigation.

In the study, which is reported in Cancer Research, the German team genetically analyzed 559 breast cancer patients and 554 healthy women all under the age of 50. It turned out that having one copy of the PROGINS allele and one normal HPR allele lowers the breast cancer risk by almost one fifth. Carrying two PROGINS copies makes the risk plummet to only 27 percent of the controls. The control group was carefully matched to the patient group with respect to age and prior exposure to known risk factors such as smoking and alcohol. Geneticist Torben A. Kruse of Odense University Hospital in Denmark, who has worked on the genetics of breast cancer, calls the study an important contribution. "In this complicated field, scientists are increasingly becoming aware of the need for good control groups and for conducting investigations in genetically homogeneous groups," he says, and to avoid effects stemming from ethnically-related genetic differences, only Caucasian women were included in this study.

Jenny Chang-Claude points out that her new findings are pieces of a much larger puzzle. "I am sure we will find that many genetic variations can affect breast cancer risk and we are only at the beginning of cataloguing them." Kruse adds that actually solving the puzzle of how such variations and mutations fit together to determine the final outcome is a daunting task that will occupy researchers for years to come. In her own study, Chang-Claude already sees hints of a complicated story. In women with a family history of breast cancer, the PROGINS variation was not protective. And when the researchers did a separate analysis taking into account the women's menopausal status, it suggested that the PROGINS mutation might only offer protection from cancers that develop before menopause. Chang-Claude speculates that this "could be due to differences in hormonal status having an influence on the effect of PROGINS."

In fact, the German team hypothesizes that the protective effect of the PROGINS gene variation is in itself linked to an interaction with female sex hormones. According to Chang-Claude, progesterone receptors encoded by a PROGINS gene might permit less progesterone to bind to these hormones. Because of the cellular pathways the receptor feeds into, the result could be a decreased activation of the receptor for estrogen. And there is some evidence that blocking estrogen receptors can protect against breast cancer. "The actual biological mechanism that makes PROGINS protective must be worked out, and hopefully it will form the basis for developing new therapies," says Chang-Claude. However, she stresses that with the limited current knowledge it is much too early to talk of any clinical applications of her findings. "There is not yet a reason for women to seek genetic testing for the PROGINS variant," she says.

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Wang-Gohrke, S., Chang-Claude, J., Becher, H., Kieback, D.G., & Runnebaum, I.B. Progesterone receptor gene polymorphism is associated with decreased risk for breast cancer by age 50. Cancer Res 60, 2348-2350 (May 1, 2000).

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