Akademik Veri Yönetim Sistemi
x. International Congress of Molecular Medicine, İzmir, Türkiye, 23 - 27 Eylül 2024, ss.59, (Özet Bildiri)
HER2-positive breast cancer, characterized by the overexpression of HER2, leads to aggressive tumor growth. Trastuzumab has significantly improved outcomes for patients; however, resistance remains a major challenge. Tumor heterogeneity, encompassing genetic, and phenotypic differences within and between tumors, complicates treatment and contributes to drug resistance. Understanding the mechanisms underlying trastuzumab resistance, such as tumor heterogeneity, is crucial for developing effective therapeutic strategies. This study investigates the role of ITGB3 heterogeneity in trastuzumab resistance, focusing on its impact on TGF-β signaling and cell migration. It also evaluates the potential of combining trastuzumab with the integrin inhibitor cilengitide to overcome resistance associated with ITGB3 levels. Trastuzumab-resistant HCC1954 and SKBR3 cell lines were generated and analyzed for ITGB3 expression heterogeneity. The impact of ITGB3 on TGF-β responsive genes and cell migration was assessed using luciferase reporter assays, real-time PCR, and migration assays. The effects of combined treatment with trastuzumab and cilengitide were also evaluated. ITGB3 expression varied significantly among resistant clones, correlating with increased expression of TGF-β responsive genes and enhanced migration markers. Combined treatment with trastuzumab and cilengitide significantly reduced TGF-β signaling and migration-related gene expression, particularly in high ITGB3-expressing cells. ITGB3 plays a critical role in trastuzumab resistance through modulation of TGF-β signaling, migration, and contributing to tumor heterogeneity. Targeting ITGB3, alone or in combination with cilengitide, offers a promising strategy to resensitize resistant HER2-positive breast cancer cells to trastuzumab. These findings provide valuable insights into the mechanisms of trastuzumab resistance and suggest potential therapeutic avenues for improving patient outcomes.