Abstract
PurposeThere remain a lack of biomarkers for endocrine therapy resistance in patients with breast cancer (BC), which is proving to be a great challenge. In vitro experiments have shown that downregulation of PTEN expression leads to resistance to tamoxifen (TAM) in BC cells. We aimed to investigate the predictive role of tumor PTEN promoter methylation and PTEN expression in long-term survival after TAM adjuvant therapy in patients with early-stage BC.MethodsFrom 2001 to 2013, 105 patients with stage I–III BC who were treated with standardized adjuvant TAM for 5 years or until relapse in West China Hospital (WCH) were enrolled in this study. PTEN expression and DNA methylation of three specified sequences from the PTEN promoter in primary tumors were measured using immunohistochemistry and pyrosequencing. A cohort of 159 hormone receptor-positive patients receiving TAM treatment from The Cancer Genome Atlas (TCGA) database was used for verification.ResultsMedian follow-up time for the WCH cohort was 141.7 months. The low, moderate, and high PTEN expression groups had differing 10-year disease-free survival (DFS) (42.3%, 55%, 81%, respectively, P = 0.027) and overall survival (OS) rates (65%, 84.2%, 90.5%, respectively, P = 0.027). Higher methylation levels of the second sequence (− 819 to − 787 bp), rather than the first (− 1143 to − 1107 bp) or third sequence (− 663 to − 593 bp), independently increased the risk of disease recurrence (hazard ratio = 2.60) and death (hazard ratio = 3.79) in the WCH cohort, according to multivariate Cox regression analysis. Importantly, out of the five CpG islands located within this sequence, only high methylation of the − 796 CpG island predicted shorter DFS and OS. In TCGA validation cohort, there was also a trend of higher methylation of the − 796 CpG island correlating with shorter disease-free intervals, with borderline significance (P = 0.057).ConclusionLow PTEN expression and high methylation of its promoter (sequence − 819 to − 787 bp) in tissue predict poor DFS and OS in hormone receptor-positive early BC patients who received adjuvant TAM.
Highlights
IntroductionFor patients with early-stage hormone receptor-positive (HR +) breast cancer (BC), 5 to 10 years of adjuvant hormone therapy can significantly slow down regional and PTEN is a major phosphatase that can halt the PI3K/AKT signaling pathway, one of the core cancer pathways [7]
For patients with early-stage hormone receptor-positive (HR +) breast cancer (BC), 5 to 10 years of adjuvant hormone therapy can significantly slow down regional and PTEN is a major phosphatase that can halt the PI3K/AKT signaling pathway, one of the core cancer pathways [7].1 3 Vol.:(0123456789)Breast Cancer Research and Treatment PTEN can dephosphorylate lipids and proteins, it has a separate role from that of a phosphatase under normal and pathological conditions
In the test cohort of West China Hospital (WCH) HR+early breast cancer (EBC) adjuvant TAMtreated patients, we found that the higher methylation level of the − 819 to − 787 sequence of the PTEN promoter was an independent predictor of outcome, including disease-free survival (DFS) and overall survival (OS)
Summary
For patients with early-stage hormone receptor-positive (HR +) breast cancer (BC), 5 to 10 years of adjuvant hormone therapy can significantly slow down regional and PTEN is a major phosphatase that can halt the PI3K/AKT signaling pathway, one of the core cancer pathways [7]. PTEN can dephosphorylate lipids and proteins, it has a separate role from that of a phosphatase under normal and pathological conditions. It plays a role in genome stability and DNA repair [8]. Deletion of gene loci, epigenetic silencing through promoter methylation, PTEN degradation, and post-translational alterations are speculated to be the main causes of PTEN inactivation [9]. The high incidence of hypermethylation of suppressor genes and hypomethylation of oncogenes makes methylation a promising biomarker and target for epigenetic therapy [11]
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