Abstract
PurposeThe protein tyrosine phosphatase, non-receptor type 2 (PTNP2) regulates receptor tyrosine kinase signalling, preventing downstream activation of intracellular pathways like the PI3K/Akt pathway. The gene encoding the protein is located on chromosome 18p11; the 18p region is commonly deleted in breast cancer. In this study, we aimed to evaluate PTPN2 protein expression in a large breast cancer cohort, its possible associations to PTPN2 gene copy loss, Akt activation, and the potential use as a clinical marker in breast cancer.MethodsPTPN2 protein expression was analysed by immunohistochemistry in 664 node-negative breast tumours from patients enrolled in a randomised tamoxifen trial. DNA was available for 146 patients, PTPN2 gene copy number was determined by real-time PCR.ResultsPTPN2 gene loss was detected in 17.8% of the tumours. Low PTPN2 protein expression was associated with higher levels of nuclear-activated Akt (pAkt-n). Low PTPN2 as well as the combination variable low PTPN2/high pAkt-n could be used as predictive markers of poor tamoxifen response.ConclusionPTPN2 negatively regulates Akt signalling and loss of PTPN2 protein along with increased pAkt-n is a new potential clinical marker of endocrine treatment efficacy, which may allow for further tailored patient therapies.
Highlights
Anti-oestrogen treatment significantly reduces the recurrence and death rates in women with oestrogen receptor (ER)-positive breast cancer
The gene copy number status of PTPN2 could be analysed in 146 available tumour samples, whereas PTPN2 protein expression could be assessed in 664 tumours
Few studies have explored the role of PTPN2 in breast cancer; we aimed to evaluate the clinical value of PTPN2 in a large breast cancer cohort
Summary
Anti-oestrogen treatment significantly reduces the recurrence and death rates in women with oestrogen receptor (ER)-positive breast cancer. Endocrine therapy is a welltolerated treatment to which most ER-positive tumours respond, around 30% of the ER-positive tumours show de novo or acquired resistance to the treatment. A commonly suggested mechanism to this resistance is the crosstalk between ER and growth factor signalling pathways, the receptor tyrosine kinase (RTK)/PI3K/Akt/ mTOR axis (Musgrove and Sutherland 2009; Miller 2013). RTK signalling consists of complex networks of proteins with numerous feedback mechanisms. Protein tyrosine phosphatases (PTP) negatively regulate RTK signalling by dephosphorylation of tyrosine residues. Genetic and/or epigenetic alterations resulting in deregulation of PTP function have been shown to contribute to the development of several diseases, including cancer (Bussieres-Marmen et al 2014; He et al 2014; Julien et al 2011)
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