Abstract
In a previous study, we detected a significant association between phosphoserine aminotransferase 1 (PSAT1) hyper-methylation and mRNA levels to outcome to tamoxifen treatment in recurrent disease. We here aimed to study the association of PSAT1 protein levels to outcome upon tamoxifen treatment and to obtain more insight in its role in tamoxifen resistance. A cohort of ER positive, hormonal therapy naïve primary breast carcinomas was immunohistochemically (IHC) stained for PSAT1. Staining was analyzed for association with patient’s time to progression (TTP) and overall response on first-line tamoxifen for recurrent disease. PSAT1 mRNA levels were also assessed by reverse transcriptase quantitative polymerase chain reaction (RT-qPCR; n = 161) and Affymetrix GeneChip (n = 155). Association of PSAT1 to biological pathways on tamoxifen outcome were assessed by global test. PSAT1 protein and mRNA levels were significantly associated to poor outcome to tamoxifen treatment. When comparing PSAT1 protein and mRNA levels, IHC and RT-qPCR data showed a significant association. Global test results showed that cytokine and JAK-STAT signaling were associated to PSAT1 expression. We hereby report that PSAT1 protein and mRNA levels measured in ER positive primary tumors are associated with poor clinical outcome to tamoxifen.
Highlights
Resistance to endocrine therapies is a major issue in recurrent estrogen receptor (ER) positive breast cancers[1]
phosphoserine aminotransferase 1 (PSAT1) expression was observed in a small subset (N = 25) of ER positive breast tumors by IHC, while the majority of cores did not show any PSAT1 expression (N = 236)
Testing for association of PSAT1 protein expression to clinical and histo-pathological parameters showed that PSAT1 expression was significantly associated with poor grade tumors (χ2 test for trend P < 0.001) and local relapse (χ2 test P = 0.009; Table 1)
Summary
Resistance to endocrine therapies is a major issue in recurrent estrogen receptor (ER) positive breast cancers[1]. We have linked hyper-methylation in the promoter region of the PSAT1 gene, a key enzyme in serine synthesis, to a favorable outcome on tamoxifen treatment; high PSAT1 mRNA levels were associated to tamoxifen resistance[10]. To that the serine biosynthetic pathway itself has been shown to be a critical factor in breast cancer tumorigenesis[11] and therapy resistance[10]. Verified the association of the biomarker to tamoxifen therapy outcome To this end, we assessed PSAT1 protein levels by IHC in a cohort of FFPE tissues and analyzed its association with tamoxifen therapy outcome. Gene expression data of a cohort of ER positive breast carcinomas was used to gain insight into the role of PSAT1 in tamoxifen resistance
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