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

Yu-Hsiang Huang ¹, Pei-Yi Chu ², Ji-Lin Chen ³, Chun-Teng Huang ⁴, Chia-Han Lee ⁵, Ka-Yi Lau ⁶, Wan-Lun Wang ⁷, Yu-Ling Wang ⁸, Pei-Ju Lien ⁹, Ling-Ming Tseng ¹⁰, Chun-Yu Liu ¹¹

Affiliations

¹ School of Medicine, National Yang-Ming University, Taipei 11221, Taiwan. yuhsiang83@gmail.com.
² Department of Pathology, Show Chwan Memorial Hospital, Changhua City 50091, Taiwan. chu.peiyi@msa.hinet.net.
³ Comprehensive Breast Health Center, Taipei Veterans General Hospital, Taipei 11217, Taiwan. jlchen_@outlook.com.
⁴ School of Medicine, National Yang-Ming University, Taipei 11221, Taiwan. DAK17@tpech.gov.tw.
⁵ Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei 11217, Taiwan. gahanleeo@gmail.com.
⁶ Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei 11217, Taiwan. cayeelau@gmail.com.
⁷ Comprehensive Breast Health Center, Taipei Veterans General Hospital, Taipei 11217, Taiwan. rabbitwang78tw@gmail.com.
⁸ Comprehensive Breast Health Center, Taipei Veterans General Hospital, Taipei 11217, Taiwan. away390@yahoo.com.tw.
⁹ Comprehensive Breast Health Center, Taipei Veterans General Hospital, Taipei 11217, Taiwan. prlain@vghtpe.gov.tw.
¹⁰ School of Medicine, National Yang-Ming University, Taipei 11221, Taiwan. lmtseng@vghtpe.gov.tw.
¹¹ School of Medicine, National Yang-Ming University, Taipei 11221, Taiwan. cyliu3@vghtpe.gov.tw.

PMID: 30154367
41 References
3 citations

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.

Keywords: CIP2A; PP2A; SET; breast cancer; tamoxifen.

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