EMORY STUDY PROVIDES FIRST BIOLOGIC EVIDENCE TO SUPPORT HYPOTHESIS THAT HIGH ENDOGENOUS ESTROGEN EXPOSURE INCREASES BREAST CANCER RISK

August 5, 1996

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The more female mice are exposed to the female hormone estrogen produced by their own body, the greater their risk for breast cancer, report researchers from the Emory University School of Medicine in the July 15 issue of Cancer Research.

The study provides the first biologic evidence to support epidemiologic and clinical hypotheses associating early exposure to circulating, endogenous (produced by one's own body) estrogen and breast cancer risk.

The researchers developed a line (model) of transgenic mice whose genetic make up had been altered to overexpess an enzyme aromatase (int-5/aromatase) which catalyzes the conversion of androgens (male sex hormones) to estrogen -- the rate limiting step in estrogen biosynthesis. Signs of precancerous and cancerous activity were apparent in the breast (mammary) tissue of every mouse in which this gene overexpressed; none of their nontransgenic litter mates showed precancerous activity, reports first author Rajeshwar Rao Tekmal, Ph.D., assistant professor of Emory's Department of Gynecology and Obstetrics, and Winship Cancer Center.

"...no studies have demonstrated the direct involvement of aromatase in the initiation of preneoplastic (precancerous) and/or neoplastic (cancerous) changes in mammary epithelium (tissue)," the authors say. "The study reported here addressed this question directly, presenting evidence for the first time that the overproduction of

int-5/aromatase in mammary glands of transgenic females leads to a range of morphological abnormalities... which are all indicative of preneoplastic changes. In contrast, we have not observed any histological (tissue) abnormalities in either nontransgenic litter mates or in a transgenic line (of mice) that had no significant overexpression of int-5/aromatase. These studies suggest clearly that the overexpression of the int-5/aromatase initiates various preneoplastic changes in mammary tissue. These changes may in turn increase the risk of developing breast neoplasia and increase susceptibility to environmental carcinogens."

The group also reports that the number of new cancer cells increases proportionally to the amount of overexpression by the estrogen precursor -- and that "these effects could be blocked completely by aromatase inhibitors."

"The ongoing studies are aimed at understanding the mechanism involved in transformation of normal tissue to neoplastic tissue, and cooperation of tumor suppressor and other oncogenes involved in breast cancer in accelerating the cancer in these animals," Dr. Tekmal says. "This model provides a very useful system to investigatre these possibilities and others such as preventive approaches to reduce the risk of breast cancer associated with endogenous estrogen by chemoprevention and dietary interventions."

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