Prepubertal estradiol and genistein exposures up-regulate BRCA1 mRNA and reduce mammary tumorigenesis.

Publisher: Irl Press At Oxford University Press Country of Publication: England NLM ID: 8008055 Publication Model: Print-Electronic Cited Medium: Print ISSN: 0143-3334 (Print) Linking ISSN: 01433334 NLM ISO Abbreviation: Carcinogenesis Subsets: MEDLINE

Publication: Oxford : Irl Press At Oxford University Press
Original Publication: [New York, IRL Press]

Sexual Maturation*; Anticarcinogenic Agents/*therapeutic use ; BRCA1 Protein/*genetics ; Estradiol/*therapeutic use ; Genistein/*therapeutic use ; Mammary Glands, Animal/*drug effects ; Mammary Neoplasms, Experimental/*prevention & control ; RNA, Messenger/*metabolism; 9,10-Dimethyl-1,2-benzanthracene ; Animals ; Cell Division/drug effects ; Female ; Mammary Glands, Animal/cytology ; Mammary Glands, Animal/physiology ; Mammary Neoplasms, Experimental/chemically induced ; Mammary Neoplasms, Experimental/pathology ; Rats ; Rats, Sprague-Dawley ; Receptors, Estrogen/metabolism ; Receptors, Progesterone/metabolism ; Up-Regulation

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 microg 17beta-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 microg 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)-alpha. 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-alpha 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.

0 (Anticarcinogenic Agents)
0 (BRCA1 Protein)
0 (RNA, Messenger)
0 (Receptors, Estrogen)
0 (Receptors, Progesterone)
4TI98Z838E (Estradiol)
57-97-6 (9,10-Dimethyl-1,2-benzanthracene)
DH2M523P0H (Genistein)

Date Created: 20040120 Date Completed: 20040614 Latest Revision: 20180228

20240829

10.1093/carcin/bgh065

14729590