Prognostic and therapeutic value of mitochondrial serine hydroxyl-methyltransferase 2 as a breast cancer biomarker

Zhang,Lahong; Chen,Zhaojun; Xue,Dan; Zhang,Qi; Liu,Xiyong; Luh,Frank; Hong,Liquan; Zhang,Hang; Pan,Feng; Liu,Yuhua; Chu,Peiguo; Zheng,Shu; Lou,Guoqiang; Yen,Yun

doi:10.3892/or.2016.5112

Prognostic and therapeutic value of mitochondrial serine hydroxyl-methyltransferase 2 as a breast cancer biomarker

Authors:
- Lahong Zhang
- Zhaojun Chen
- Dan Xue
- Qi Zhang
- Xiyong Liu
- Frank Luh
- Liquan Hong
- Hang Zhang
- Feng Pan
- Yuhua Liu
- Peiguo Chu
- Shu Zheng
- Guoqiang Lou
- Yun Yen
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Affiliations: Department of Laboratory Medicine, Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang 310015, P.R. China, Department of Plastic Surgery, Second Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang 310009, P.R. China, Hangzhou Hope Biotechnology Inc., Hangzhou, Zhejiang 310015, P.R. China, Biomarker Development, California Cancer Institute, Temple City, CA 91780, USA, Taipei Medical University, School of Medicine, Taipei 110, Taiwan, R.O.C., Cancer Institute, Zhejiang University, Hangzhou, Zhejiang 310009, P.R. China, Department of Pathology, City of Hope National Medical Center, Duarte, CA 91010, USA, Sino-American Cancer Foundation, Temple City, CA 91780, USA, Taipei Medical University, Taipei 110, Taiwan, R.O.C.
Published online on: September 20, 2016 https://doi.org/10.3892/or.2016.5112
Pages: 2489-2500
Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Mitochondrial serine hydroxylmethyltransferase 2 (SHMT2) is a key enzyme in the serine/glycine synthesis pathway. SHMT2 has been implicated as a critical component for tumor cell survival. The aim of the present study was to evaluate the prognostic value and efficiency of SHMT2 as a biomarker in patients with breast cancer. Individual and pooled survival analyses were performed on five independent breast cancer microarray datasets. Gene signatures enriched by SHMT2 were also analyzed in these datasets. SHMT2 protein expression was detected using immunohistochemistry (IHC) assay in 128 breast cancer cases. Gene set enrichment analysis revealed that SHMT2 was significantly associated with gene signatures of mitochondrial module, cancer invasion, metastasis and poor survival among breast cancer patients (p<0.05). The clinical relevance of SHMT2 was validated on IHC data. The mitochondrial localization of SHMT2 protein was visualized on IHC staining. Independent and pooled analysis confirmed that SHMT2 expression was associated with breast cancer tumor aggressiveness (TNM staging and Elson grade) in a dose-dependent manner (p<0.05). The prognostic performance of SHMT2 mRNA was comparable to other gene signatures and proved superior to TNM staging. Further analysis results indicated that SHMT2 had better prognostic value for estrogen receptor (ER)-negative breast cancer patients, compared to ER-positive patients. In cases involving stage IIb breast cancer, chemotherapy significantly extended survival time among patients with high SHMT2 expression. These results indicate that SHMT2 may be a valuable prognostic biomarker in ER-negative breast cancer cases. Furthermore, SHMT2 may be a potential target for breast cancer treatment and drug discovery.

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