title: 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.affiliation: Department of Clinical and Experimental Medicine, and Department of Oncology, Linköping University, 58185, Linköping, Sweden, elin.karlsson@liu.se.
authors.forename: Elin
authors.initials: E
authors.lastname: Karlsson
authors.forename: Cynthia
authors.initials: C
authors.lastname: Veenstra
authors.forename: Shad
authors.initials: S
authors.lastname: Emin
authors.forename: Chhanda
authors.initials: C
authors.lastname: Dutta
authors.forename: Gizeh
authors.initials: G
authors.lastname: Pérez-Tenorio
authors.forename: Bo
authors.initials: B
authors.lastname: Nordenskjöld
authors.forename: Tommy
authors.initials: T
authors.lastname: Fornander
authors.forename: Olle
authors.initials: O
authors.lastname: Stål
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology / Q000627:therapeutic use; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D017353:Gene Deletion; D018628:Gene Dosage; D015870:Gene Expression; D006801:Humans; D008207:Lymphatic Metastasis; D011379:Prognosis; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2 / Q000172:deficiency* / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D016019:Survival Analysis; D013629:Tamoxifen / Q000494:pharmacology* / Q000627:therapeutic use; D047368:Tumor Burden
chemical_list: D018931:Antineoplastic Agents, Hormonal; D014408:Biomarkers, Tumor; D012333:RNA, Messenger; D013629:Tamoxifen; D051057:Proto-Oncogene Proteins c-akt; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2