Potential Biomarkers Associated with Prognosis and Trastuzumab Response in HER2+ Breast Cancer

REDONDO, ANALIA L; CASTRO-GUIJARRO, ANA CARLA; SANCHEZ, ANGEL MATIAS; FLAMINI, MARINA INÉS

Mendoza

Simposio; III Simposio Internacional de Medicina Traslacional; 2023

Introduction: Breast cancer (BC) is the most common malignancy among women. Around 15-20% of BC overexpressed the HER2 receptor, associated with a worse prognosis. Therefore, anti-HER2 drugs have been developed, such as trastuzumab (Tz), ado-trastuzumab-emtansine (T-DM1), and lapatinib (Lp). Although Tz is the standard treatment, resistance remains a significant challenge.Objectives: To determine the actions of anti-HER2 drugs, alone or as a combined treatment (CT), in tumor progression and to identify biomarkers that allow prediction of disease progression (prognostic) and the efficacy of Tz-therapy (predictive).Methodologies: By bioinformatics, using GEO, PANTHER, and STRING tools, we selected proteins of interest to be studied. We determined how their expression, localization, and the process they modulate were affected by anti-HER2 treatments using western blots, immunofluorescence, adhesion, and migration assays. We assess their value as biomarkers using KM and ROC-plotter. We established a Tz-resistant cell model to evaluate the potential biomarkers' expression and their role in Tz-response.Results: We identified deregulated genes associated with cell motility in Tz-resistant cells. We showed that CT efficiently decreases cell adhesion and migration. We found that CT induced nuclear FAK and perinuclear cortactin localization. We observed that proteins essential for metastasis, such as SRC, FAK, and paxillin were downregulated after CT. We evidenced that vinculin and cortactin mRNA levels predict patients' survival rates and Tz-response. Finally, we noted that vinculin and cortactin are overexpressed in Tz-resistant cells and are involved in Tz-response of BC cells.Conclusions: We demonstrate the superiority of CT over monodrugs. Low doses of Tz/T-DM1+Lp efficiently inhibit adhesion and migration by downregulating critical proteins and affecting their localization. We identify vinculin and cortactin as potentially prognostic and predictive biomarkers promising for personalized BC management that would avoid Tz-therapy failure. Furthermore, we propose that vinculin and cortactin could be targeted targets in treating Tz-resistant BC cells.