Potential biomarkers associated with prognosis and trastuzumab response in HER2+ breast cáncer.

REDONDO, A; CASTRO GUIJARRO, AC; SANCHEZ, AM; FLAMINI, MI

Mendoza

Simposio; III Simposio Internacional de Medicina Traslacional; 2023

Hospital Universitario de la Universidad Nacional de Cuyo (Mendoza, Argentina).

Introduction: Breast cancer (BC) is the most common malignancy among women. Around 25% of BC overexpressed the HER2 receptor, associated with a worse prognosis. Therefore, anti-HER2 drugs have been developed like trastuzumab (Tz), ado-trastuzumab-emtansine (T-DM1), and lapatinib (Lp). Although Tz is the standard treatment, resistance still affects a significant population and is currently a major challenge in clinical oncology. Objectives: To determine the actions of anti-HER2 drugs, alone or as a combined treatment (CT), in tumor progression and to identify biomarkers (BM) that allowed predict disease progression (prognostic-BM) and the efficacy of Tz-therapy (predictive-BM).Methodologies: By bioinformatics using GEO, PANTHER, and STRING tools, we selected a set of proteins of interest to be studied. After that, 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. Next, we assess their value as BM using KM and ROC-plotter. Finally, we established a model of Tz-resistant cells to evaluate the expression of the potential biomarkers and their role in Tz-response.Resultados: We identified deregulated genes associated with cell motility in Tz-resistant cells. We showed that CT efficiently decrease cell adhesion and migration. We also found that CT induced nuclear FAK nuclear and perinuclear cortactin localization. In parallel, we observed that proteins essential for metastasis like SRC, FAK, and paxillin were downregulated after CT. We evidenced that vinculin and cortactin mRNA levels predicts survival rates and Tz-response in patients. 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 con CT than 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 BM promising for personalized BC management that would avoid Tz-therapy faillure. Furthermore, we propose that vinculin and cortactin could be a prompted target in the treatment of Tz-resistant BC cells.