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

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 (r s = 0.456, p < 0.0001) and PTEN protein staining (r s = 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.Electronic supplementary materialThe online version of this article (doi:10.1007/s10549-017-4160-5) contains supplementary material, which is available to authorized users.

Divergent Activity of the Pseudogene PTENP1 in ER-Positive and Negative Breast Cancer

“…Upregulated PTENP1 was associated with significantly higher PTEN gene expression and PTEN protein levels, thus indicating close coregulation of PTEN and PTENP1 mRNA levels. Although these data are consistent with those in our recent publication demonstrating a significant correlation between PTEN and PTENP1 gene expression in 317 locally advanced breast cancers, that clinical study has found no association between PTENP1 mRNA and PTEN protein levels (7). In line with these findings, upregulated PTENP1 3 0 UTR did not influence PTEN protein expression in either of the breast cancer xenograft models assessed in the current work.…”

“…In line with these findings, upregulated PTENP1 3 0 UTR did not influence PTEN protein expression in either of the breast cancer xenograft models assessed in the current work. Whereas PTEN has been examined by IHC in our previous clinical study (7) and was examined by Western blotting herein, PTEN protein analysis was performed by reverse-phase protein array in the TCGA dataset, thus potentially explaining the lack of correlation between PTENP1 gene expression and PTEN protein levels that we observed.…”

“…We have recently reported expression of PTENP1 in 222 of 318 locally advanced human breast cancer samples, with a significant correlation between PTENP1 and PTEN mRNA levels (7). However, we established that PTENP1 gene levels have no prognostic value, whereas high PTEN gene expression is associated with poor survival among patients with estrogen receptor (ER)-positive and TP53 wt tumors (7). On the basis of these findings, we hypothesized that the functional role of PTEN and PTENP1 may depend on the hormone receptor status of breast cancer.…”

Opposite Prognostic Impact of Single PTEN-loss andPIK3CAMutations in Early High-risk Breast Cancer

“…This finding is related to our previous observation in a different cohort of patients treated in the pre-trastuzumab era (16), where PIK3CA mutation types interacted with PTEN status and affected outcome in opposite directions. Further in breast cancer, TP53 mutation status may influence the prognostic CANCER GENOMICS & PROTEOMICS 16: 195-206 (2019) 202 effect of PIK3CA mutations (25) and of preserved PTEN (34), while the unfavourable effect of PTEN-loss may be augmented in the presence of additional alterations interfering with the activation of the PI3K pathway (35). All this argumentation suggests that we need to shift our view from single oncogenic drivers to a molecular environment that certainly interferes with-and may alter the effects of these drivers (36).…”

Long non‐coding NR2F1‐AS1 is associated with tumor recurrence in estrogen receptor‐positive breast cancers

“…HOTAIR has been proposed as predictive marker for metastatic progression and overall survival in early-stage tumors of breast cancer (Gupta et al, 2010). On the other hand, NEAT1 and PTENP1, commonly known as tumor suppressors in various cancer types, have been shown to potentiate cell growth and tumor progression in breast cancer (Ke et al, 2016;Yndestad et al, 2017;Yndestad et al, 2018). Collectively, these nuances emphasize the tissue/ cell specificity of lncRNAs and their ability to selectively target genes and impact signaling cascades in a confined manner.…”