Abstract
e11135 Background: Trastuzumab is an antibody that blocks the activity of HER2, a member of epidermal growth factor receptor family that is amplified in approximately 20% of breast cancer patients. Trastuzumab significantly improves disease-free and overall survival in these cases. Nevertheless, many patients become resistant to this antibody. Methods: Different human breast cancer cell lines MCF7, SKBR3 and a stable transfected heparanase-1 cDNA MCF7 cells (HPSE-1-MCF7), as well a non tumoral cell line, MCF10A were used for the experimental assays of cell viability, confocal immunofluorescence microscopy and quantitative RT-PCR analysis. Results: Our findings show the role of some extracellular matrix (ECM) components in trastuzumab resistance using breast cancer cell lines assays. MCF7 cells were transfected with heparanase-1 (HPSE-1) cDNA and became completely resistant to trastuzumab. HPSE-1 transfection changes the glycosaminoglycans profile in the transfected MCF7 cells, suggesting that glycosaminoglycans/proteoglycans could be involved in the resistance process. The results showed that trastuzumab binds to heparan sulfate (HS) and this effect is necessary to antibody activity. It was also demonstrated that trastuzumab decreases heparanases isoforms (HPSE-1, HPSE-2), HER2 and the proteoglycan syndecan-1 (Syn-1) mRNA expression in MCF7 cell line, while in MCF7 HPSE-1 transfected cells trastuzumab increases mRNA expression of these molecules. SKBR3 cells presented the highest expression levels of these molecules. The relative proportion of HS chains in Syn-1 core protein seems to influence MCF7 cells sensibility and resistance to this antibody. In addition, HPSE-1/HER2 ratio seems to define trastuzumab resistance, once the relative increase in HPSE-1 expression decrease breast cancer cells sensitivity to trastuzumab. Conclusions: These new insights show the effect of ECM components for trastuzumab efficacy and could be useful when devising strategies for overcoming drug resistance in HER2+ cancers.
Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
