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

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.

Proteomic Analysis on Anti-Proliferative and Apoptosis Effects of Curcumin Analog, 1,5-bis(4-Hydroxy-3-Methyoxyphenyl)-1,4-Pentadiene-3-One-Treated Human Glioblastoma and Neuroblastoma Cells

“…Protein SET, formerly known as Oncoprotein 17, was downregulated in MS13-treated U-87 MG and SH-SY5Y. Notably, the overexpression of SET has been associated with poor prognosis, high recurrence rate, and chemoresistance (Cristóbal et al, 2015) in several types of cancer including lung (Liu et al, 2015), glioblastoma (He et al, 2016), breast (Huang et al, 2018), and pancreas (Bhutia et al, 2013). By inhibiting the protein phosphatase 2A (PP2A) activity, SET interferes with the tumor suppressor function of PP2A.…”

Kynurenine 3-monooxygenase upregulates pluripotent genes through β-catenin and promotes triple-negative breast cancer progression

“…Immunohistochemical staining procedure has been described [22]. Briefly, primary antibodies against KMO (LS-C165595, LSBio, Seattle, WA, USA), CD44 (#3570), b-catenin (#8480S) and Nanog (#4903; Cell Signaling) were used at 1:100 dilution for overnight incubation.…”

Redox inhibition of protein phosphatase PP2A: Potential implications in oncogenesis and its progression

“…Sens et al have reported that PP2A inactivation may also result from the haploinsufficient loss of PPP2R4 (PTPA) gene which enhances PP2A activity by binding with the catalytic subunit of PP2A [125]. Furthermore, overexpression or deregulated activation of the endogenous inhibitor SET/I2PP2A is also frequently observed in cancers [126], [127], [128], [129], [130], [131], [132], [133], [134], [135], [136]. The SET protein has been reported to directly interact with the catalytic subunit of PP2A, thereby impeding its activity [137].…”