SET Overexpression is Associated with Worse Recurrence-Free Survival in Patients with Primary Breast Cancer Receiving Adjuvant Tamoxifen Treatment

Yu-Hsiang Huang,Chia-Han Lee,Chun-Teng Huang,Wan-Lun Wang,Yu-Ling Wang,Ling-Ming Tseng,Chun-Yu Liu,Pei-Yi Chu,Pei-Ju Lien,Ji-Lin Chen,Ka-Yi Lau

doi:10.3390/jcm7090245

Abstract

Adjuvant tamoxifen reduces the recurrence rate of estrogen receptor (ER)-positive breast cancer. Previous in vitro studies have suggested that tamoxifen can affect the cancerous inhibitor of protein phosphatase 2A (CIP2A)/protein phosphatase 2A (PP2A)/phosphorylation Akt (pAkt) signaling in ER-negative breast cancer cells. In addition to CIP2A, SET nuclear proto-oncogene (SET) oncoprotein is another intrinsic inhibitor of PP2A, participating in cancer progression. In the current study, we explored the clinical significance of SET, CIP2A, PP2A, and Akt in patients with ER-positive breast cancer receiving adjuvant tamoxifen. A total of 218 primary breast cancer patients receiving adjuvant tamoxifen with a median follow-up of 106 months were analyzed, of which 17 (7.8%) experienced recurrence or metastasis. In an immunohistochemical (IHC) stain, SET overexpression was independently associated with worse recurrence-free survival (RFS) (hazard ratio = 3.72, 95% confidence interval 1.26–10.94, p = 0.017). In silico analysis revealed mRNA expressions of SET, PPP2CA, and AKT1 significantly correlated with worse RFS. In vitro, SET overexpression reduced tamoxifen-induced antitumor effects and drove luciferase activity in an Estrogen receptor element (ERE)-dependent manner. In conclusion, SET is a prognostic biomarker in patients with primary ER-positive breast cancer receiving adjuvant tamoxifen and may contribute to the failure of the tamoxifen treatment by modulating the ER signaling. Our study warrants further investigation into the potential role of SET in ER-positive breast cancer.

Highlights

Estrogen receptor (ER)-positive breast cancer accounts for 70% of breast cancer subtypes and, despite its relatively good prognostic tumor biology, harbors a substantial and constant risk of recurrence after the primary resection, even after five years of treatment [1,2,3]
We aimed to investigate the associations of four biomarkers, including SET, cancerous inhibitor of protein phosphatase 2A (CIP2A), phosphatase 2A (PP2A), and Akt, with recurrence-free survival in ER-positive breast cancer patients receiving adjuvant tamoxifen therapy
We examined 218 ER-positive specimens collected from primary breast cancer patients with a median age of 50.6 years

Summary

Introduction

Estrogen receptor (ER)-positive breast cancer accounts for 70% of breast cancer subtypes and, despite its relatively good prognostic tumor biology, harbors a substantial and constant risk of recurrence after the primary resection, even after five years of treatment [1,2,3]. Adjuvant hormonal therapies, such as tamoxifen and aromatase inhibitors, have significantly reduced the risk of recurrence in patients with ER-positive early breast cancers [4,5]. The usefulness of these multi-gene testing techniques suggests that molecular markers may help to identify patients at risk and select patients who could benefit most from hormonal therapy

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