Effect of PTP1B phosphatase inhibitor in HER2positive breast cancer

CÓRDOBA, MARIA EVELYN ; NADIN S; CUELLO CARRIÓN FD; FANELLI M.A*

Congreso; Reunión Cientifica Anual de la Sociedad de Biología de Cuyo; 2022

The interference of the HER2 signaling pathway through monoclonal antibodies and tyrosine-kinase inhibitors constitutes a strategy in the treatment of HER2-positive (HER2+) breast cancer (BC). Our previous studies showed that HER2+ tumors with plasma membrane–associated β-catenin expression and without monoclonal antibody therapy (Trastuzumab, Tzb) had significantly better overall survival. The protein tyrosine phosphatase PTP1B plays an important role in BC and is also required for HER2/Neu-driven BC in mice. PTP1B binds to β-catenin keeping it located in the plasma membrane. We observed by copy number variation (CNV) analysis of β-catenin (CTNNB1) and PTP1B (PTPN1) from HER2 enriched BC patients using the TCGA database, that PTPN1 tended to be amplified in HER2+ patients while CTNNB1was downregulated. Also, these genetic changes were associated with PTPN1 expression levels. This study aimed to evaluate PTP1B role in cell migration, and spheroid growth in SKBR3 and MCF7 HER2+ cell lines treated with Tzb, heregulin (Hrg growth factor), and α-Bromo-4-hydroxyacetophenone (PTP1B inhibitor). Cell migration was evaluated by wound healing assay and cell growth by 3D cultured spheroids. Concerning viability, SKBR3 cells overexpressing HER2 were more sensitive to Tzb than MCF7 cells in 2D cultures. For MCF7, the viability of 2D and 3D cultures with Tzb were similar while SKBR3 3D culture was more resistant than 2D culture. In SKBR3 cells, Hrg treatment promoted 3D culture growth and migration, while Tzb and the PTP1B inhibitor stopped the spheroids growth and decreased cell migration. On the contrary, in MCF7 cells, none of the treatments affected spheroids growth and cell migration. Cell growth arrest and decreased cell migration in SKBR3 cells by inhibition of PTP1B and blocking of HER2 signaling pathway was observed. We conclude that PTP1B can be an interesting molecular target for HER2+ human breast cancer.