Abstract
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. Cancer Gene Therapy (2001) 8, 759–770
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References
Feunteun J . Breast cancer and genetic instability: the molecules behind the scenes Mol Med Today 1998 4: 263–267
Miki Y, Swensen J, Shattuck-Eidens D, et al . A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1 Science 1994 266: 66–71
Callebaut I, Mornon JP . From BRCA1 to RAP1: a widespread BRCT module closely associated with DNA repair FEBS Lett 1997 400: 25–30
Koonin VF, Altschul SF, Bork P . BRCA1 protein products: functional motifs Nat Genet 1998 13: 266–267
Wilson CA, Ramos L, Villaseñor MR, et al . Localization of human BRCA1 and its loss in high-grade, non-inherited breast carcinomas Nat Genet 1999 21: 236–240
Scully R, Chen JJ, Plug A, et al . Association of BRCA1 with Rad51 in mitotic and meiotic cells Cell 1997 88: 265–275
Zhong Q, Chen CF, Li S, et al . Association of BRCA1 with the hRad50–hMre11–p95 complex and the DNA damage response Science 1999 285: 747–750
Cortez D, Wang Y, Qin J, et al . Requirement of ATM-dependent phosphorylation of BRCA1 in the DNA damage response to double-strand breaks Science 1999 286: 1162–1166
Wang Y, Cortez D, Yazdi P, et al . BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures Genes Dev 2000 14: 927–939
Lee JS, Collins KM, Brown AL, et al . hCds1-mediated phosphorylation of BRCA1 regulates the DNA damage response Nature 2000 404: 201–204
Anderson SE, Schlegel BP, Nakajima T, et al . BRCA1 protein is linked to the RNA polymerase II holoenzyme complex via RNA helicase a Nat Genet 1998 19: 254–256
Abbott DW, Thompson ME, Robinson-Benion C, et al . BRCA1 expression restores radiation resistance in BRCA1-defective cancer cells through enhancement of transcription-coupled DNA repair J Biol Chem 1999 274: 18808–18812
Le Page F, Kwoh EE, Avrutskaya A, et al . Transcription-coupled repair of 8-oxoguanine: requirement for XPG, TFIIH, and CSB and implications for Cockayne syndrome Cell 2000 101: 159–171
Le Page F, Randrianarison V, Marot D, et al . BRCA1 and BRCA2 are necessary for the transcription-coupled repair of the oxidative 8-oxoguanine lesion in human cells Cancer Res 2000 60: 5548–5552
Somasundaram K, Zhang HB, Zeng YX, et al . Arrest of the cell cycle by the tumour-suppressor BRCA1 requires the CDK-inhibitor p21WAF1/CiP1 Nature 1997 389: 187–190
Zhang HB, Somasundaram K, Peng Y, et al . BRCA1 physically associates with p53 and stimulates its transcriptional activity Oncogene 1998 16: 1713–1721
Ouchi T, Monteiro ANA, August A, et al . BRCA1 regulates p53-dependent gene expression Proc Natl Acad Sci USA 1998 95: 2302–2306
Pao GM, Janknecht R, Ruffner H, et al . CBP/p300 interact with and function as transcriptional coactivators of BRCA1 Proc Natl Acad Sci USA 2000 97: 1020–1025
Hu YF, Hao ZL, Li R . Chromatin remodeling and activation of chromosomal DNA replication by an acidic transcriptional activation domain from BRCA1 Genes Dev 1999 13: 637–642
Chen YM, Farmer AA, Chen CF, et al . BRCA1 is a 220-kDa nuclear phosphoprotein that is expressed and phosphorylated in a cell cycle-dependent manner Cancer Res 1996 56: 3168–3172
Campbell M, Aprelikova ON, Van der Meer R, et al . Construction and characterization of recombinant adenoviruses expressing human BRCA1 or murine Brca1 genes Cancer Gene Ther 2001 8: 231–239
MacLachlan TK, Somasundaram K, Sgagias M, et al . BRCA1 effects on the cell cycle and the DNA damage response are linked to altered gene expression J Biol Chem 2000 275: 2777–2785
Xu X, Weaver Z, Linke SP, et al . Centrosome amplification and a defective G2-M cell cycle checkpoint induce genetic instability in BRCA1 exon 11 isoform–deficient cells Mol Cell 1999 3: 389–395
Shao NS, Chai YL, Shyam E, et al . Induction of apoptosis by the tumor suppressor protein BRCA1 Oncogene 1996 13: 1–7
Harkin DP, Bean JM, Miklos D, et al . Induction of GADD45 and JNK/SAPK-dependent apoptosis following inducible expression of BRCA1 Cell 1999 97: 575–586
Thompson ME, Jensen RA, Obermiller PS, et al . Decreased expression of BRCA1 accelerates growth and is often present during sporadic breast cancer progression Nat Genet 1995 9: 444–450
Rao VN, Shao NS, Ahmad M, et al . Antisense RNA to the putative tumor suppressor gene BRCA1 transforms mouse fibroblasts Oncogene 1996 12: 523–528
Holt JT, Thompson ME, Szabo C, et al . Growth retardation and tumour inhibition by BRCA1 Nat Genet 1996 12: 298–302
Aprelikova ON, Fang BS, Meissner EG, et al . BRCA1-associated growth arrest is RB-dependent Proc Natl Acad Sci USA 1999 96: 11866–11871
Benard J, Da Silva J, De Blois MC, et al . Characterization of a human ovarian adenocarcinoma line, IGROV1, in tissue culture and in nude mice Cancer Res 1985 45: 4970–4979
Foray N, Randrianarison V, Marot D, et al . Gamma-rays-induced death of human cells carrying mutations of BRCA1 or BRCA2 Oncogene 1999 18: 7334–7342
Fajac A, Da Silva J, Ahomadegbe JC, et al . Cisplatin-induced apoptosis and p53 gene status in a cisplatin-resistant human ovarian carcinoma cell line Int J Cancer 1996 68: 67–74
Tomlinson GE, Chen TTL, Stastny VA, et al . Characterization of a breast cancer cell line derived from a germ-line BRCA1 mutation carrier Cancer Res 1998 58: 3237–3242
Estreicher A, Iggo R . Retrovirus-mediated p53 gene therapy Nat Med 1996 2: 1163
Wersto RP, Rosenthal ER, Seth PK, et al . Recombinant, replication-defective adenovirus gene transfer vectors induce cell cycle dysregulation and inappropriate expression of cyclin proteins J Virol 1998 72: 9491–9502
Somasundaram K, MacLachlan TK, Burns TF, et al . BRCA1 signals ARF-dependent stabilization and coactivation of p53 Oncogene 1999 18: 6605–6614
Xu XL, Wagner KU, Larson D, et al . Conditional mutation of Brca1 in mammary epithelial cells results in blunted ductal morphogenesis and tumour formation Nat Gen 1999 22: 37–43
Tait DL, Obermiller PS, Hatmaker AR, et al . Ovarian cancer BRCA1 gene therapy: phase I and II trial differences in immune response and vector stability Clin Cancer Res 1999 5: 1708–1714
Tait DL, Obermiller PS, Redlin-Frazier S, et al . A phase I trial of retroviral BRCA1sv gene therapy in ovarian cancer Clin Cancer Res 1997 3: 1959–1968
Holt JT, Thompson ME, Szabo C, et al . Growth retardation and tumor inhibition by BRCA1 (correction) Nat Genet 1998 19: 102
Fan SJ, Wang JA, Yuan RQ, et al . BRCA1 as a potential human prostate tumor suppressor: modulation of proliferation, damage responses and expression of cell regulatory proteins Oncogene 1998 16: 3069–3082
Barboule N, Baldin V, Jozan S, et al . Increased level of p21 in human ovarian tumors is associated with increased expression of cdk2, cyclin A and PCNA Int J Cancer 1998 76: 891–896
Santoso JT, Tang DC, Lane SB, et al . Adenovirus-based p53 gene therapy in ovarian cancer [see comments] Gynecol Oncol 1995 59: 171–178
Schreiber M, Muller WJ, Singh G, et al . Comparison of the effectiveness of adenovirus vectors expressing cyclin kinase inhibitors p16INK4A, p18INK4C, p19INK4D, p21(WAF1/CIP1) and p27KIP1 in inducing cell cycle arrest, apoptosis and inhibition of tumorigenicity Oncogene 1999 18: 1663–1676
Dameron KM, Volpert OV, Tainsky MA, et al . The p53 tumor suppressor gene inhibits angiogenesis by stimulating the production of thrombospondin Cold Spring Harbor Symp Quant Biol 1994 59: 483–489
Acknowledgements
We thank Arlette Vervisch (Cytometry laboratory — CNRS) for her excellent technical assistance in cell cycle analysis, Patrice Ardouin for his help in animal care, Vladimir Lazar for a major contribution in sequencing, and Nazanine Modtjahedi for stimulating discussions. This work was supported by CRC contract 97-07 from Institut Gustave-Roussy and a Contrat Libre (No. 9023) from ARC. N.F was supported by postdoctoral fellowships from the Fondation pour la Recherche Médicale (FRM) and from Electricité de France (Département de Radioprotection).
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Randrianarison, V., Marot, D., Foray, N. et al. BRCA1 carries tumor suppressor activity distinct from that of p53 and p21. Cancer Gene Ther 8, 759–770 (2001). https://doi.org/10.1038/sj.cgt.7700366
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DOI: https://doi.org/10.1038/sj.cgt.7700366
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