The tumor suppressor activity induced by adenovirus-mediated BRCA1 overexpression is not restricted to breast cancers.
The BRCA1 (breast cancer 1) breast cancer susceptibility gene is recognized as responsible for most familial breast and ovarian cancers and is suggested to be a tissue-specific tumor suppressor gene. In this report, we investigated the tissue specificity of tumor inhibitory activities induced by a recombinant adenovirus coding for wild-type BRCA1 (wtAdBRCA1). We demonstrated a pronounced in vitro antiproliferative effect on H1299 lung and HT29 colon cells upon infection with AdBRCA1. We describe a prolonged G1 cell cycle arrest associated with a decrease in the hyperphosphorylated form of Rb, suggesting that the Rb/E2F pathway is implicated in BRCA1-induced cell growth arrest. We also observed a significant antitumor effect in these pre-established subcutaneous tumors after in situ delivery of AdBRCA1, although these two tumors do not express wt p53, and also estrogen alpha and beta, progesterone and androgen receptors. Moreover, BRCA1 can induce a strong prolonged cell cycle arrest and apoptotic cell death but no significant antiangiogenic effect in H1299 tumors. Finally, our data indicate that intratumor administration of wtAdBRCA1 significantly inhibits growth of lung and colon steroid hormone-independent tumors.
Marot
D
D
UMR 8121 CNRS, Vectorologie et Transfert de gènes, Institut Gustave Roussy, Villejuif Cedex, France. marot@igr.fr
Opolon
P
P
Brailly-Tabard
S
S
Elie
N
N
Randrianarison
V
V
Connault
E
E
Foray
N
N
Feunteun
J
J
Perricaudet
M
M
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000628:therapy*; D005260:Female; D016193:G1 Phase; D015972:Gene Expression Regulation, Neoplastic; D019398:Genes, BRCA1; D016147:Genes, Tumor Suppressor; D020022:Genetic Predisposition to Disease; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000235:genetics; D019073:HT29 Cells; D006801:Humans; D015552:Injections, Intralesional; D008175:Lung Neoplasms / Q000628:therapy*; D008297:Male; D051379:Mice; D009368:Neoplasm Transplantation; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism
D016160:Retinoblastoma Protein