PAI1 Regulates Cell Morphology and Migration Markers in Trastuzumab-Resistant HER2-Positive Breast Cancer Cells
Asiye Busra Boz Er1, Idris Er2
1Department of Medical Biology, Faculty of Medicine, Recep Tayyip Erdogan University, Rize 53200, Turkey.
Abstract:
HER2-positive breast cancer is a significant cause of mortality. Overcoming trastuzumab resistance requires a deeper understanding of its molecular mechanisms to develop effective therapies. This study investigates the role of plasminogen activator inhibitor-1 (PAI1) in migration and drug resistance in trastuzumab-resistant HER2-positive breast cancer. Trastuzumab resistance poses a significant challenge in clinical management due to its association with aggressive disease behaviour and limited treatment options. This study focuses on PAI1, a key player in the TGF-β signalling pathway, which is implicated in cancer progression and metastasis. Trastuzumab-resistant cell lines (SKBR3 and HCC1954) demonstrated markedly elevated PAI1 expression levels, up to 40-fold compared to parental lines. This elevation was accompanied by increased expression of migration markers such as Col4a1, Fibronectin, ICAM1, Timp2, and Vimentin. Through overexpression and silencing experiments, we observed that modulating PAI1 levels significantly impacts cell morphology, transitioning cells from an epithelial to mesenchymal phenotype. Importantly, combining trastuzumab with aleplasinin, a PAI1 inhibitor, synergistically reduced PAI1 expression in both parental and resistant cell lines. This suggests a potential therapeutic strategy to overcome trastuzumab resistance. These findings emphasise PAI1 as a critical mediator of migration and therapeutic response in HER2-positive breast cancer, offering insights into novel treatment approaches targeting PAI1 to improve clinical outcomes in drug resistance.
Insights
Plasminogen activator inhibitor-1 (PAI1) drives migration and trastuzumab resistance in HER2-positive breast cancer. Inhibiting PAI1 with aleplasinin alongside trastuzumab shows therapeutic promise for overcoming drug resistance.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- HER2-positive breast cancer is a leading cause of cancer mortality.
- Trastuzumab resistance presents a major clinical challenge, necessitating research into underlying molecular mechanisms.
- Understanding resistance pathways is crucial for developing more effective therapeutic strategies.
Purpose of the Study:
- To investigate the role of plasminogen activator inhibitor-1 (PAI1) in trastuzumab resistance and cell migration in HER2-positive breast cancer.
- To explore PAI1 as a potential therapeutic target for overcoming trastuzumab resistance.
Main Methods:
- Analysis of PAI1 expression in trastuzumab-resistant HER2-positive breast cancer cell lines (SKBR3, HCC1954).
- Assessment of migration markers and cell morphology changes following PAI1 modulation (overexpression and silencing).
- Evaluation of the synergistic effect of combining trastuzumab with the PAI1 inhibitor aleplasinin.
Main Results:
- Trastuzumab-resistant cell lines exhibited significantly elevated PAI1 expression (up to 40-fold).
- Increased PAI1 correlated with enhanced expression of migration markers and a shift towards a mesenchymal phenotype.
- Co-treatment with trastuzumab and aleplasinin synergistically reduced PAI1 levels in both sensitive and resistant cells.
Conclusions:
- PAI1 is a critical mediator of migration and contributes to trastuzumab resistance in HER2-positive breast cancer.
- Targeting PAI1 with inhibitors like aleplasinin represents a promising strategy to overcome therapeutic resistance.
- These findings offer insights into novel treatment approaches to improve outcomes for patients with resistant HER2-positive breast cancer.
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