Carcinogenesis Advance Access originally published online on January 16, 2004
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Carcinogenesis, Vol. 25, No. 5, 741-748,
May 2004
Carcinogenesis vol.25 no.5 © Oxford University Press 2004; all rights reserved.
ARTICLE |
Prepubertal estradiol and genistein exposures up-regulate BRCA1 mRNA and reduce mammary tumorigenesis
Lombardi Cancer Center and Department of Oncology, Georgetown University, 3970 Reservoir Road NW, Washington, DC 20007, USA and 1 Department of Medical Nutrition, Karolinska Institute, Huddinge 14186, Sweden
2 To whom correspondence should be addressed at: Research Building, Lombardi Cancer Center, Room W405, Georgetown University, 3970 Reservoir Road NW, Washington, DC 20057, USA Tel: +1 202 687-7237; Fax: +1 202 687 7505; Email: clarkel{at}georgetown.edu
Prepubertal exposure to soy or its biologically active component genistein reduces later breast cancer risk in both animal models and human populations. We investigated whether that might be due to reported estrogenic properties of genistein. Our study indicated that daily prepubertal exposures between postnatal days 7 and 20 to 10 µg 17ß-estradiol (E2) reduced later risk of developing 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary tumors. Assessment of mammary gland morphology revealed that both prepubertal E2 and genistein (50 µg daily) exposures reduced the size of mammary epithelial area and number of terminal end buds (TEBs) and increased the density of lobulo-alveolar structures, suggesting that these exposures induced elimination of targets for malignant transformation by differentiation. Next, the mechanisms mediating the protective effects of E2 and genistein were investigated. E2 is shown to up-regulate BRCA1, a tumor suppressor gene that participates in DNA damage repair processes and cell differentiation and that down-regulates the activity of estrogen receptor (ER)-
. The expression of BRCA1 mRNA was up-regulated in the mammary glands of rats exposed to E2 or genistein during prepuberty, when determined at the ages of 3, 8 and 16 weeks. Prepubertal E2 exposure reduced ER- levels in the mammary gland, while prepubertal genistein exposure had an opposite effect. Our results suggest that prepubertal estrogenic exposures may reduce later breast cancer risk by inducing a persistent up-regulation of BRCA1 in the mammary gland.
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