E2F3b over-expression in ovarian carcinomas and in BRCA1 Haploinsufficient fallopian tube epithelium
| Autor: | Rochelle L. Garcia, Piri Welcsh, Elizabeth M. Swisher, Kathy Agnew, Na Lu Smith, Joshua Z. Press |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
Adult
Cancer Research animal structures endocrine system diseases Context (language use) Haploinsufficiency Biology medicine.disease_cause Article Epithelium Germline Genetics medicine Humans Protein Isoforms RNA Messenger RNA Small Interfering skin and connective tissue diseases Fallopian Tubes Aged Ovarian Neoplasms Intraepithelial neoplasia Oncogene BRCA1 Protein Histocytochemistry Gene Amplification Middle Aged female genital diseases and pregnancy complications medicine.anatomical_structure E2F3 Transcription Factor Cancer research Female Tumor Suppressor Protein p53 Carcinogenesis Fallopian tube |
| Zdroj: | Genes, Chromosomes and Cancer. 51:1054-1062 |
| ISSN: | 1045-2257 |
| Popis: | We have previously shown that the E2F3 oncogene is up-regulated as part of a “preneoplastic expression profile” in fallopian tube epithelium of women with BRCA1 mutations. We studied E2F3 expression in fallopian tube epithelium and carcinomas of women with BRCA1 or BRCA2 mutations or wildtype for both genes. Significantly more foci of TP53 positive cells in histologically normal fallopian tube epithelium from women with BRCA1 mutations but not in wildtype or BRCA2 mutated individuals had E2F3 protein overexpression relative to adjacent normal fallopian tube epithelium, 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 wildtype 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 fallopian tube epithelium 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 fallopian tube epithelium 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 pre-neoplastic event in fallopian tube epithelium from BRCA1 mutation carriers. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Plný text