Tyrosine Phosphatase PTPRO Deficiency in ERBB2-Positive Breast Cancer Contributes to Poor Prognosis and Lapatinib Resistance

Abstract

Despite the initial benefit from treating ERBB2-positive breast cancer with tyrosine kinase inhibitor lapatinib, resistance develops inevitably. Since the expression of protein tyrosine phosphatase receptor-type O (PTPRO), a member of the R3 subfamily of receptor protein tyrosine phosphatases (PTPs), is inversely correlated with the aggressiveness of multiple malignancies, we decided to explore the correlation between PTPRO and lapatinib resistance in ERBB2-positive breast cancer. Results of immunohistochemical (IHC) staining and the correlation analysis between the expression levels of PTPRO and the clinicopathological parameters indicate that PTPRO is downregulated in cancer tissues as compared with normal tissues and negatively associated with differentiation, tumor size, tumor depth, as well as the expression of ERBB2 and Ki67. Results from Kaplan–Meier analyses indicate that lower expression of PTPRO is correlated with shorter relapse-free survival for patients with ERBB2-positive breast cancer, and multivariable Cox regression analysis found that PTPRO can potentially serve as an independent prognostic indicator for ERBB2-positive breast cancer. Results from both human breast cancer cells with PTPRO knockdown or overexpression and mouse embryonic fibroblasts (MEFs) which derived from Ptpro+/+ and Ptpro−/− mice with then stably transfected plasmid FUGW-Erbb2 consistently demonstrated the essentiality of PTPRO in the lapatinib-mediated anticancer process. Our findings suggest that PTPRO is not only able to serve as an independent prognostic indicator, but upregulating PTPRO can also reverse the lapatinib resistance of ERBB2-positive breast cancer.

PTPRO-related CD8+ T-cell signatures predict prognosis and immunotherapy response in patients with breast cancer

“…Immunohistochemistry (IHC) staining was performed as previously described ( 18 , 19 ). In brief, 4-µm sections from representative breast cancer tumor tissue were cut from formalin-fixed paraffin-embedded specimens and underwent deparaffinization, rehydration, endogenous peroxidase blocking, and antigen retrieval.…”

“…The intensity of staining was scored using the following scales: 1, weak staining; 2, moderate staining; and 3, strong staining. The percentage ( P ) and intensity ( I ) of the cytoplasm or membrane expression were multiplied to generate a numerical score ( S = P * I ), which was modified from previous studies ( 19 ).…”

“…The protein tyrosine phosphatases (PTPs) catalyze the dephosphorylation of specific target protein tyrosine kinases (PTKs) as a common means of regulating cellular signal transduction and play an important regulatory role in immune cell signaling ( 15 , 16 ). Protein tyrosine phosphatase receptor type O (PTPRO), a member of the PTP family, has been reported that it can function as a tumor suppressor and prognostic factor in various cancers ( 16 – 19 ). Furthermore, downregulation of PTPRO by aberrant hypermethylation in various cancer types, including lung cancer, hepatocellular carcinoma (HCC), breast cancer, esophageal cancer, and leukemia, suggests that it may be a therapeutic candidate for epigenetic therapy ( 20 – 24 ).…”

Protein tyrosine kinase inhibitor resistance in malignant tumors: molecular mechanisms and future perspective

“…It suggests that epigenetics is responsible for PTPRO downregulation. 137 Interestingly, protein phosphatase 2 (PP2A) is a serine/threonine phosphatase and negatively regulates several signaling pathways. Previously it was shown that the expression levels of cellular inhibitors of PP2A (CIP2A) and novel splice variants of CIP2A are associated with sensitivity to imatinib in myeloid leukemia.…”

Dose-sparing effect of lapatinib co-administered with a high-fat enteral nutrition emulsion: preclinical pharmacokinetic study

“…Lapatinib is an oral small-molecule tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR) and Erb-B2 receptor tyrosine kinase 2 (ERBB2 or HER2). It competitively blocks the ATP-binding of the receptors’ intracellular tyrosine kinase domain, preventing the phosphorylation of receptors and inhibiting tumor cell proliferation ( Dong et al, 2022 ; Yu et al, 2022 ). The combination of lapatinib with capecitabine has been approved for treating advanced or metastatic HER2-positive breast cancer patients who have progressed following standard therapy, including anthracyclines, taxanes, and trastuzumab ( de Azambuja et al, 2014 ).…”