Overexpression of Caspase-3s Splice Variant in Locally Advanced Breast Carcinoma Is Associated with Poor Response to Neoadjuvant Chemotherapy
| Autor: | Claire Oudin, Jean-Marc Riedinger, Sarab Lizard-Nacol, Frédérique Végran, Romain Boidot, Franck Bonnetain |
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| Rok vydání: | 2006 |
| Předmět: |
Cancer Research
Cyclophosphamide medicine.medical_treatment Apoptosis Breast Neoplasms Biology medicine.disease_cause Breast cancer Antineoplastic Combined Chemotherapy Protocols Tumor Cells Cultured medicine Humans Epirubicin Enzyme Precursors Chemotherapy Caspase 3 Carcinoma Ductal Breast Alternative splicing Transfection Middle Aged medicine.disease Caspase Inhibitors Neoadjuvant Therapy Alternative Splicing Gene Expression Regulation Oncology Chemotherapy Adjuvant Drug Resistance Neoplasm Caspases Disease Progression Cancer research Female Fluorouracil Carcinogenesis Breast carcinoma medicine.drug |
| Zdroj: | Clinical Cancer Research. 12:5794-5800 |
| ISSN: | 1557-3265 1078-0432 |
| Popis: | Purpose: CASP-3 gene gives rise, by alternative splicing to a caspase-3s variant, to the antagonist apoptotic property of caspase-3. Deregulation of splicing in tumor cells favoring the expression of antiapoptotic variants has been reported to contribute to both tumorigenesis and chemoresistance. Thus, we investigated the role of caspase-3 and its splice variant in breast cancer cells. Experimental Design: Breast tumor cell lines deficient (MCF-7) and proficient (HBL100) for CASP-3 gene were transfected with each transcript and were characterized for their apoptotic response to cyclophosphamide. Expression of the two transcripts were measured by reverse transcription-PCR in 130 breast carcinomas, including 90 locally advanced tumors treated with neoadjuvant chemotherapy containing cyclophosphamide, epirubicine, and 5-fluorouracil. Results: Overexpression of caspase-3s variant in caspase-3–transfected cell lines significantly inhibits apoptosis induced by cyclophosphamide (P < 0.0001 for both cell lines). In breast tissues, only caspase-3 levels were higher in carcinomas than in corresponding adjacent normal tissues (P = 0.0396). Locally advanced carcinomas with high levels of caspase-3 (P < 0.0001) and weak levels of caspase-3s (P = 0.0248) were more sensitive to treatment. Therefore, increase in caspase-3s/caspase3 ratio expression was significantly associated with chemoresistance (P = 0.01). Logistic univariate and multivariate analyses realized according to pathologic response confirm that increased caspase-3s expression was indicative of chemoresistance (P = 0.012 and P = 0.026, respectively). Conclusions: The results agree with an antagonist function between the two transcripts of caspase-3 and show that their ratio of expression levels may define a subset of locally advanced breast cancer patients who are more likely to benefit from neoadjuvant cyclophosphamide-containing chemotherapy. |
| Databáze: | OpenAIRE |
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