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Trastuzumab Down-Regulates Bcl-2 Expression and Potentiates Apoptosis Induction by Bcl-2/Bcl-X_L Bispecific Antisense Oligonucleotides in HER-2Gene–Amplified Breast Cancer Cells

¹ Division of Medical Oncology A, ² Laboratory of Experimental Preclinical Chemotherapy, ³ Laboratory B, ⁴ Division of Pathology, and ⁵ Division of Clinical Pathology, Regina Elena National Cancer Institute, Rome, Italy; and ⁶ Department of Oncology, University of Zurich, Zurich, Switzerland

Purpose: To investigate the possible existence of an antiapoptotic cross-talk between HER-2 and antiapoptotic Bcl-2 family members.

Experimental Design: Bcl-2 and Bcl-X_L expression and apoptosis induction were analyzed in HER-2gene–amplified (BT474) and nonamplified (ZR 75-1) breast cancer cell lines exposed to trastuzumab, alone or in combination with either Bcl-2/Bcl-X_L bispecific antisense oligonucleotides (AS-4625) or the small-molecule Bcl-2 antagonist HA14-1.

Results: In addition to HER-2 and epidermal growth factor receptor, trastuzumab down-regulated Bcl-2, but not Bcl-X_L, protein, and mRNA expression in BT474 cells. Interestingly, trastuzumab-induced down-regulation of HER-2 and Bcl-2 was also observed in three of five and two of three breast cancer patients undergoing trastuzumab treatment, respectively. Despite Bcl-2 down-regulation, however, trastuzumab only marginally increased the rate of apoptosis (7.3 ± 3.5%). We therefore investigated whether a combination of AS-4625 and trastuzumab might increase proapoptotic efficiency. AS-4625 treatment of BT474 cells decreased both Bcl-2 and Bcl-X_L expression, resulting in a 21 ± 7% net apoptosis induction; the combination of AS-4625 followed by trastuzumab resulted in a significantly stronger induction of apoptosis (37 ± 6%, P < 0.01) that was not observed with the reverse treatment sequence (trastuzumab followed by AS-4625). Similar results were obtained with the Bcl-2 antagonist HA14-1; indeed, exposure of BT474 cells to HA14-1 followed by trastuzumab resulted in a striking proapoptotic synergism (combination index = 0.58 ± 0.18), as assessed by isobologram analysis.

Conclusions: Altogether our findings suggest that combined targeting of HER-2 and Bcl-2 may represent a novel, rational approach to more effective breast cancer therapy.

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