BRCA1 carries tumor suppressor activity distinct from that of p53 and p21.
The loss of BRCA1 function appears as an essential step in breast and ovarian epithelial cells oncogenesis and is consistent with the concept that BRCA1 acts as a tumor suppressor gene. However, the mechanism underlying this activity is not understood. In 1996, a retroviral vector was used for BRCA1 delivery to demonstrate that the transfer of BRCA1 inhibits breast and ovarian cancer cell growth. Since this early observation, the tumor growth inhibitory activity of BRCA1 in vivo has not been further documented. Here we re-address this issue and report experiments designed to evaluate the potential of adenovirus-mediated BRCA1 delivery to suppress the growth of cells with various status of endogenous BRCA1 in comparison with p53 and p21. Delivery of wild-type BRCA1 by an adenovirus vector in breast and ovarian tumor cells, decreases in vitro proliferation and tumorigenicity. Similarly, in vivo administration of BRCA1 provokes tumor growth retardation or regression comparable to that obtained with p53 or p21. The antitumor effect of BRCA1 is not observed upon transfer of a mutant lacking the 542 C-terminal residues. The p53- or p21-mediated antiproliferative activities are likely to bear on their capacity to induce apoptosis and/or interfere with cell cycle checkpoint. By contrast, the data presented here show that neither of these mechanisms can account for the BRCA1-mediated antitumor activity and suggest the activation of an alternative route.
Randrianarison
V
V
Laboratoire de Vectorologie et Transfert de gènes, CNRS UMR 1582, Institut Gustave Roussy, 94805 Villejuif Cedex, France.
Marot
D
D
Foray
N
N
Cabannes
J
J
Méret
V
V
Connault
E
E
Vitrat
N
N
Opolon
P
P
Perricaudet
M
M
Feunteun
J
J
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D019313:BRCA1 Protein / Q000235:genetics* / Q000378:metabolism; D002453:Cell Cycle; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D016147:Genes, Tumor Suppressor / Q000502:physiology*; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D015674:Mammary Neoplasms, Animal / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D017384:Sequence Deletion; D015533:Transcriptional Activation; D014162:Transfection; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
D019313:BRCA1 Protein; C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D016159:Tumor Suppressor Protein p53