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 ovari an epithelial cells oncogenesis and is consistent with the concept that BRC A1 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 ova rian cancer cell growth. Since this early observation, the tumor growth inh ibitory activity of BRCA1 in vivo has not been further documented. Here we re-address this issue and report experiments designed to evaluate the poten tial of adenovirus-mediated BRCA1 delivery to suppress the growth of cells with various status of endogenous BRCA1 in comparison with p53 and p21. Del ivery of wild-type BRCA1 by an adenovirus vector in breast and ovarian tumo r cells, decreases in vitro proliferation and tumorigenicity. Similarly, in vivo administration of BRCA1 provokes tumor growth retardation or regressi on comparable to that obtained with p53 or p21. The antitumor effect of BRC A1 is not observed upon transfer of a mutant lacking the 542 C-terminal res idues. The p53- or p21-mediated anti proliferative activities are likely to bear on their capacity to induce apoptosis and/or interfere with cell cycl e checkpoint. By contrast, the data presented here show that neither of the se mechanisms can account for the BRCA1-mediated antitumor activity and sug gest the activation of an alternative route.