High PTEN gene expression is a negative prognostic marker in human primary breast cancers with preserved p53 function

Synnøve Yndestad,Per Eystein Lønning,Ranjan Chrisanthar,Stian Knappskog,Eilin Austreid,Hans Petter Eikesdal,Peer Kåre Lilleng

doi:10.1007/s10549-017-4160-5

Abstract

PurposePTEN is an important tumor suppressor in breast cancer. Here, we examined the prognostic and predictive value of PTEN and PTEN pseudogene (PTENP1) gene expression in patients with locally advanced breast cancer given neoadjuvant chemotherapy.MethodsThe association between pretreatment PTEN and PTENP1 gene expression, response to neoadjuvant chemotherapy, and recurrence-free and disease-specific survival was assessed in 364 patients with locally advanced breast cancer given doxorubicin, 5-fluorouracil/mitomycin, or epirubicin versus paclitaxel in three phase II prospective studies. Further, protein expression of PTEN or phosphorylated Akt, S6 kinase, and 4EBP1 was assessed in a subgroup of 187 tumors.ResultsNeither PTEN nor PTENP1 gene expression level predicted response to any of the chemotherapy regimens tested (n = 317). Among patients without distant metastases (n = 282), a high pretreatment PTEN mRNA level was associated with inferior relapse-free (RFS; p = 0.001) and disease-specific survival (DSS; p = 0.003). Notably, this association was limited to patients harboring TP53 wild-type tumors (RFS; p = 0.003, DSS; p = 0.009). PTEN mRNA correlated significantly with PTENP1 mRNA levels (rs = 0.456, p < 0.0001) and PTEN protein staining (rs = 0.163, p = 0.036). However, no correlation between PTEN, phosphorylated Akt, S6 kinase or 4EBP1 protein staining, and survival was recorded. Similarly, no correlation between PTENP1 gene expression and survival outcome was observed.ConclusionHigh intratumoral PTEN gene expression was associated with poor prognosis in patients with locally advanced breast cancers harboring wild-type TP53.

Highlights

Mutations in the TP53 tumor suppressor gene, encoding the p53 protein, are associated with lack of response to anthracycline- and mitomycin-containing chemotherapy as well as poor prognosis in breast cancer [1,2,3,4,5,6,7]
PTENP1 gene expression, response to neoadjuvant chemotherapy, and recurrence-free and disease-specific survival was assessed in 364 patients with locally advanced breast cancer given doxorubicin, 5-fluorouracil/mitomycin, Electronic supplementary material The online version of this article contains supplementary material, which is available to authorized users
Among patients without distant metastases (n = 282), a high pretreatment PTEN mRNA level was associated with inferior relapse-free (RFS; p = 0.001)

Summary

Introduction

Mutations in the TP53 tumor suppressor gene, encoding the p53 protein, are associated with lack of response to anthracycline- and mitomycin-containing chemotherapy as well as poor prognosis in breast cancer [1,2,3,4,5,6,7]. PI3K-Akt-mTOR signaling is involved in resistance to endocrine- and HER2-directed therapy clinically [9, 11], as well as resistance to chemotherapy in preclinical trials [12, 13]. This suggests that PTEN expression may influence response to cancer treatment. While PTEN somatic mutations are rare, PTEN protein expression is frequently lost in breast carcinomas, pointing to transcriptional and post-transcriptional regulation as possible mechanisms [14, 15]. In vitro data from prostate cancer cell lines suggest that PTEN pseudogene (PTENP1) mRNA transcripts may regulate the PTEN expression level by competing for PTEN-degrading micro RNAs (miRNAs) [17]

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