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

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.

• Authors: Elin Karlsson, Cynthia Veenstra, Shad Emin, Chhanda Dutta, Gizeh Pérez-Tenorio, Bo Nordenskjöld, Tommy Fornander, Olle Stål
• Journal: Breast cancer research and treatment (Breast Cancer Res Treat) Vol. 153 Issue 1 Pg. 31-40 (Aug 2015) ISSN: 1573-7217 [Electronic] Netherlands
• PMID: 26208487 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents, Hormonal
• Biomarkers, Tumor
• RNA, Messenger
• Tamoxifen
• Proto-Oncogene Proteins c-akt
• Protein Tyrosine Phosphatase, Non-Receptor Type 2

Topics

• Antineoplastic Agents, Hormonal (pharmacology, therapeutic use)
• Biomarkers, Tumor
• Breast Neoplasms (drug therapy, genetics, metabolism, mortality, pathology)
• Drug Resistance, Neoplasm (genetics)
• Female
• Gene Deletion
• Gene Dosage
• Gene Expression
• Humans
• Lymphatic Metastasis
• Prognosis
• Protein Tyrosine Phosphatase, Non-Receptor Type 2 (deficiency, genetics)
• Proto-Oncogene Proteins c-akt (metabolism)
• RNA, Messenger (genetics)
• Survival Analysis
• Tamoxifen (pharmacology, therapeutic use)
• Tumor Burden