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Overexpression of Caspase-3s Splice Variant in Locally Advanced Breast Carcinoma Is Associated with Poor Response to Neoadjuvant Chemotherapy

Authors' Affiliations: ¹ Laboratory of Molecular Genetics, Institut National de la Sante et de la Recherche Medicale U-517; ² Laboratory of Medical Biology; and ³ Department of Medical Information, Centre Georges François Leclerc, Dijon, France

Requests for reprints: Sarab Lizard-Nacol, Laboratory of Molecular Genetics, Centre Georges François Leclerc, 1, rue du professeur Marion, 21034 Dijon cedex, France. Phone: 33-3-80-73-77-58; Fax: 33-3-80-73-77-26; E-mail: SLizard{at}dijon.fnclcc.fr.

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.