title: E2F3b over-expression in ovarian carcinomas and in BRCA1 haploinsufficient fallopian tube epithelium.
abstract: We have previously shown that the E2F3 oncogene is up-regulated as part of a "preneoplastic expression profile" in fallopian tube epithelium (FTE) of women with BRCA1 mutations. We studied E2F3 expression in FTE and carcinomas of women with BRCA1 or BRCA2 mutations or wildtype for both genes. Significantly more foci of TP53 positive cells in histologically normal FTE from women with BRCA1 mutations but not in wildtype or BRCA2 mutated individuals had E2F3 protein overexpression relative to adjacent normal FTE, which occurred in the context of focally increased proliferation, potentially explaining the increased neoplastic potential of tubal TP53 foci in women with BRCA1 mutations. To assess mechanisms of E2F3 deregulation in ovarian or tubal carcinogenesis, we studied E2F3 and its two isoforms E2F3a and E2F3b in wild-type ovarian carcinomas and ovarian carcinomas associated with germline BRCA1 and BRCA2 mutations. The expression of E2F3b, but not E2F3a, was correlated with the expression of BRCA1 in all three genetic groups. In primary cultures of FTE from women with BRCA1 mutation or wildtype for BRCA1 and BRCA2, siRNA-induced BRCA1 deficiency led to increased E2F3b but not E2F3a expression. Our results suggest that E2F3b and BRCA1 are functionally connected, and BRCA1 haploinsufficiency in normal FTE may lead to up-regulation of E2F3b and increased proliferation before the development of intraepithelial neoplasia. These data support that E2F3b up-regulation is an important preneoplastic event in FTE from BRCA1 mutation carriers.
authors.affiliation: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Washington School of Medicine, Seattle, 98195, USA.
authors.forename: Na Lu
authors.initials: NL
authors.lastname: Smith
authors.forename: Piri
authors.initials: P
authors.lastname: Welcsh
authors.forename: Joshua Z
authors.initials: JZ
authors.lastname: Press
authors.forename: Kathy J
authors.initials: KJ
authors.lastname: Agnew
authors.forename: Rochelle
authors.initials: R
authors.lastname: Garcia
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Swisher
mesh_terms: D000328:Adult; D000368:Aged; D019313:BRCA1 Protein / Q000235:genetics* / Q000378:metabolism; D050699:E2F3 Transcription Factor / Q000096:biosynthesis* / Q000235:genetics* / Q000378:metabolism; D004848:Epithelium / Q000378:metabolism; D005187:Fallopian Tubes / Q000378:metabolism*; D005260:Female; D005784:Gene Amplification / Q000235:genetics; D057895:Haploinsufficiency; D006651:Histocytochemistry; D006801:Humans; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism; D020033:Protein Isoforms; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D050699:E2F3 Transcription Factor; C098319:E2F3 protein, human; D020033:Protein Isoforms; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53