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1.
Gene Ther ; 13(3): 235-44, 2006 Feb.
Article in English | MEDLINE | ID: mdl-16208422

ABSTRACT

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.


Subject(s)
Adenoviridae/genetics , Colonic Neoplasms/therapy , Genes, BRCA1 , Genetic Therapy/methods , Genetic Vectors/administration & dosage , Lung Neoplasms/therapy , Animals , Apoptosis , Cell Cycle , Cell Line, Tumor , Female , G1 Phase , Gene Expression Regulation, Neoplastic , Genes, Tumor Suppressor , Genetic Predisposition to Disease , Genetic Vectors/genetics , HT29 Cells , Humans , Injections, Intralesional , Male , Mice , Neoplasm Transplantation , Retinoblastoma Protein/genetics , Retinoblastoma Protein/metabolism
2.
Cancer Gene Ther ; 8(10): 759-70, 2001 Oct.
Article in English | MEDLINE | ID: mdl-11687899

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.


Subject(s)
BRCA1 Protein/genetics , Cyclins/genetics , Genes, Tumor Suppressor/physiology , Mammary Neoplasms, Animal/therapy , Ovarian Neoplasms/therapy , Tumor Suppressor Protein p53/genetics , Adenoviridae/genetics , Animals , Apoptosis , BRCA1 Protein/metabolism , Cell Cycle , Cyclin-Dependent Kinase Inhibitor p21 , Cyclins/metabolism , Female , Genetic Therapy/methods , Humans , Mammary Neoplasms, Animal/metabolism , Mammary Neoplasms, Animal/pathology , Mice , Mice, Nude , Ovarian Neoplasms/metabolism , Ovarian Neoplasms/pathology , Sequence Deletion , Transcriptional Activation , Transfection , Tumor Cells, Cultured , Tumor Suppressor Protein p53/metabolism
3.
Cancer Res ; 60(19): 5548-52, 2000 Oct 01.
Article in English | MEDLINE | ID: mdl-11034101

ABSTRACT

The breast and ovarian cancer susceptibility genes, BRCA1 and BRCA2, are likely to participate in DNA lesion processing. Oxidative lesions, such as 8-oxoguanine, occur in DNA after endogenous or exogenous oxidative stress. We show that deficiency for either BRCA1 or BRCA2 in human cancer cells leads to a block of the RNA polymerase II transcription machinery at the 8-oxoguanine site and impairs the transcription-coupled repair of the lesion, leading to a high mutation rate. Expression of wild-type BRCA1 from a recombinant adenovirus fully complements the repair defect in BRCA1-deficient cells. These results represent the first demonstration of the essential contribution of BRCA1 and BRCA2 gene products in the repair of the 8-oxoguanine oxidative damage specifically located on the transcribed strand in human cells. This suggests that cells from individuals predisposed to breast and/or ovarian cancer may undergo a high rate of mutations because of the deficiency of this damage repair pathway after oxidative stress.


Subject(s)
BRCA1 Protein/physiology , DNA Repair/physiology , Guanine/analogs & derivatives , Guanine/metabolism , Neoplasm Proteins/physiology , Transcription Factors/physiology , Transcription, Genetic/physiology , Adenoviridae/genetics , BRCA1 Protein/biosynthesis , BRCA1 Protein/deficiency , BRCA2 Protein , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Cell Line, Transformed , DNA Damage , DNA Repair/genetics , Female , Fibroblasts/metabolism , Fibroblasts/physiology , Genes, BRCA1/physiology , Genetic Vectors , Germ-Line Mutation , Humans , Neoplasm Proteins/deficiency , Neoplasm Proteins/genetics , Oxidative Stress , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/metabolism , RNA Polymerase II/antagonists & inhibitors , Recombinant Proteins/biosynthesis , Recombinant Proteins/genetics , Transcription Factors/deficiency , Transcription Factors/genetics , Transcription, Genetic/genetics , Transfection
4.
Oncogene ; 18(51): 7334-42, 1999 Dec 02.
Article in English | MEDLINE | ID: mdl-10602489

ABSTRACT

There is now evidence to suggest that BRCA1 and BRCA2 are involved in the response of cells to DNA damage and cell cycle checkpoint control. This report examines the death pathways of human cells with various BRCA1 and BRCA2 genotypes after exposure to gamma-rays. A lack of functional BRCA1 and BRCA2 led to defective repair of DNA double-strand breaks in irradiated cells. This impairment resulted in a relaxation of cell cycle checkpoints, production of micronuclei, and a loss of proliferative capacity. Heterozygous BRCA1 and BRCA2 mutations also led to enhanced radiosensitivity, with an impaired proliferative capacity after irradiation. The existence of a phenotype related to radiosensitivity in BRCA1+/- and BRCA2+/- cells raises the question of the response of heterozygous women to radiation.


Subject(s)
BRCA1 Protein/genetics , Cell Death/genetics , Neoplasm Proteins/genetics , Transcription Factors/genetics , BRCA2 Protein , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Breast Neoplasms/radiotherapy , Cell Death/radiation effects , DNA Damage/radiation effects , DNA Repair/radiation effects , Female , Humans , Mutation , Tumor Cells, Cultured
5.
Hum Gene Ther ; 8(17): 2103-15, 1997 Nov 20.
Article in English | MEDLINE | ID: mdl-9414258

ABSTRACT

Human adenovirus (HAV) serotypes 2 and 5 are commonly used as vector backbones for adenovirus-mediated gene transfer. However, HAVs were chosen as a backbone for the vectors for historical reasons and have a number of significant disadvantages when used as a shuttle for gene transfer in humans. As an initial trial to circumvent some of the shortcomings of HAV vectors, we have produced an E1-deleted canine adenovirus type 2 (CAV-2) vector for gene transfer. Initially, we demonstrated that CAV-2 undergoes an abortive viral cycle in a wide range of human-derived cell lines. Second, we assayed human sera containing HAV-5 neutralizing antibodies for their ability to inhibit CAV-2-induced plaques on permissive cells. In the cohort tested, our data demonstrate that the humoral response directed against HAV-5 does not inhibit CAV-2 plaque formation in the majority of cases. Canine cell lines expressing the E1 region of CAV-2 were generated and characterized. A recombinant CAV vector (CAVRSVbetagal) deleted in the E1 region and harboring lacZ was constructed. We show that CAVRSVbetagal is able to transduce and direct expression of the transgene in vitro in a variety of mammalian cells, most notably primary human-derived cells. In addition, gene transfer is demonstrated in vivo using chick embryos.


Subject(s)
Adenovirus E1 Proteins/genetics , Adenoviruses, Canine/genetics , Gene Transfer Techniques , Genetic Vectors , Transgenes , 3T3 Cells , Adenoviruses, Canine/physiology , Animals , Cell Line , Chlorocebus aethiops , Dogs , Gene Deletion , Gene Expression , HeLa Cells , Humans , Mice , Transfection , Vero Cells , beta-Galactosidase/genetics
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