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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This work was supported by grants from The Swedish Cancer Society (#13 0435) and The Swedish Research Council (A0346701).
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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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DOI: https://doi.org/10.1007/s10549-015-3516-y