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Loss of protein tyrosine phosphatase, non-receptor type 2 is associated with activation of AKT and tamoxifen resistance in breast cancer

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Abstract

Breast cancer is a heterogeneous disease and new clinical markers are needed to individualise disease management and therapy further. Alterations in the PI3K/AKT pathway, mainly PIK3CA mutations, have been shown frequently especially in the luminal breast cancer subtypes, suggesting a cross-talk between ER and PI3K/AKT. Aberrant PI3K/AKT signalling has been connected to poor response to anti-oestrogen therapies. In vitro studies have shown protein tyrosine phosphatase, non-receptor type 2 (PTPN2) as a previously unknown negative regulator of the PI3K/AKT pathway. Here, we evaluate possible genomic alterations in the PTPN2 gene and its potential as a new prognostic and treatment predictive marker for endocrine therapy benefit in breast cancer. PTPN2 gene copy number was assessed by real-time PCR in 215 tumour samples from a treatment randomised study consisting of postmenopausal patients diagnosed with stage II breast cancer 1976–1990. Corresponding mRNA expression levels of PTPN2 were evaluated in 86 available samples by the same methodology. Gene copy loss of PTPN2 was detected in 16 % (34/215) of the tumours and this was significantly correlated with lower levels of PTPN2 mRNA. PTPN2 gene loss and lower mRNA levels were associated with activation of AKT and a poor prognosis. Furthermore, PTPN2 gene loss was a significant predictive marker of poor benefit from tamoxifen treatment. In conclusion, genomic loss of PTPN2 may be a previously unknown mechanism of PI3K/AKT upregulation in breast cancer. PTPN2 status is a potential new clinical marker of endocrine treatment benefit which could guide further individualised therapies in breast cancer.

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Abbreviations

AKT:

v-AKT murine thymoma viral oncogene homologue

APP:

Amyloid precursor protein

BCS:

Breast cancer-specific survival

CMF:

Cyclophosphamide-methotrexate-5-fluorouracil

DRFS:

Distant recurrence-free survival

EGFR:

Epidermal growth factor receptor

ER:

Oestrogen-receptor

HER2:

Human epidermal growth factor receptor 2

IR:

Insulin receptor

JAK/STAT:

Janus kinase/signal transducers and activators of transcription

PI3K:

Phosphatidylinositol 3-kinase

PTEN:

Phosphatase and tensin homologue

PTPN2:

Protein tyrosine phosphatase, non-receptor type 2

RT:

Radiotherapy

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Acknowledgments

This work was supported by grants from The Swedish Cancer Society (#13 0435) and The Swedish Research Council (A0346701).

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Authors and Affiliations

  1. Department of Clinical and Experimental Medicine, and Department of Oncology, Linköping University, 58185, Linköping, Sweden

    Elin Karlsson, Cynthia Veenstra, Shad Emin, Chhanda Dutta, Gizeh Pérez-Tenorio, Bo Nordenskjöld & Olle Stål

  2. Department of Oncology, Karolinska University Hospital and Karolinska Institute, 17176, Stockholm, Sweden

    Tommy Fornander

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  1. Elin Karlsson
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  2. Cynthia Veenstra
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Correspondence to Olle Stål.

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Karlsson, E., Veenstra, C., Emin, S. et al. Loss of protein tyrosine phosphatase, non-receptor type 2 is associated with activation of AKT and tamoxifen resistance in breast cancer. Breast Cancer Res Treat 153, 31–40 (2015). https://doi.org/10.1007/s10549-015-3516-y

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