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A new targeting approach for breast cancer gene therapy using the human fatty acid synthase promoter
- Source :
- Acta Oncologica. 46:773-781
- Publication Year :
- 2007
- Publisher :
- Informa UK Limited, 2007.
-
Abstract
- Gene therapy with adenoviral vectors is a promising new approach for the treatment of refractory advanced breast cancer. Strategies to restrict adenoviral-mediated therapeutic gene expression are important to avoid harming normal cells. Fatty acid synthase (FAS) is overexpressed in several human cancers. FAS is highly expressed in infiltrating breast cancer tissue, and always associated with malignant phenotypes and poor prognosis. In this study, expression of the FAS was evaluated in three breast cancer cell lines. A 680 bp-FAS promoter was cloned and its transcriptional activity was analyzed in breast cancer cell lines. We made a recombinant adenovirus construct carrying herpes simplex virus thymidine kinase (HSV-TK) driven by human FAS promoter (Ad-FAS-TK) and analyzed its target cytotoxicity in vitro and in vivo against human breast cancer cells combined with prodrug ganciclovir (GCV). The results show that the expression of FAS varies in the three breast cancer cell lines examined (respectively, SK-Br3>MCF-7>MDA-MB-231), but FAS promoter can initiate relative high transcriptional activities in all three kinds of cancer cells while little in normal fibroblast cells. Furthermore, FAS promoter can drive the therapeutic gene in a wider range of human breast cancers than cerbB2 promoter and exhibit a stronger activity than midkine (MK) promoter. Combination of Ad-FAS-TK and GCV treatment exhibited strong-targeted cytotoxic effect on breast cancer cells but showed little activity in normal fibroblast cells. The tumorigenic capability of breast cancer cells treated with Ad-FAS-TK/GCV was completely inhibited in vitro and in vivo assays. In conclusion, adenoviral-mediated suicide gene therapy controlled by tumor associated-FAS promoter can induce specific cytotoxic effect on human breast cancer cells in vitro and in vivo. So it is a promising target for the development of gene therapy against breast cancers.
- Subjects :
- Recombinant Fusion Proteins
Genetic enhancement
Genetic Vectors
Gene Expression
Antineoplastic Agents
Breast Neoplasms
In Vitro Techniques
Biology
Breast cancer
medicine
Humans
Cytotoxic T cell
Radiology, Nuclear Medicine and imaging
Treatment Failure
Ganciclovir
Midkine
Adenoviruses, Human
Tumor Suppressor Proteins
Genes, Transgenic, Suicide
Nuclear Proteins
Cancer
Genetic Therapy
Hematology
General Medicine
Suicide gene
Prognosis
medicine.disease
Molecular biology
DNA-Binding Proteins
Phenotype
Treatment Outcome
Oncology
Thymidine kinase
Cancer cell
biology.protein
Cancer research
Female
Fatty Acid Synthases
Subjects
Details
- ISSN :
- 1651226X and 0284186X
- Volume :
- 46
- Database :
- OpenAIRE
- Journal :
- Acta Oncologica
- Accession number :
- edsair.doi.dedup.....60def641f8741d8e25fb3381d15a1770