Prognostic and therapeutic value of mitochondrial serine hydroxyl-methyltransferase 2 as a breast cancer biomarker.
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.
Department of Laboratory Medicine, Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang 310015, P.R. China.
Lahong
L
Zhang
Department of Laboratory Medicine, Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang 310015, P.R. China.
Zhaojun
Z
Chen
Department of Plastic Surgery, Second Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang 310009, P.R. China.
Dan
D
Xue
Hangzhou Hope Biotechnology Inc., Hangzhou, Zhejiang 310015, P.R. China.
Qi
Q
Zhang
Biomarker Development, California Cancer Institute, Temple City, CA 91780, USA.
Xiyong
X
Liu
Taipei Medical University, School of Medicine, Taipei 110, Taiwan, R.O.C.
Frank
F
Luh
Department of Laboratory Medicine, Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang 310015, P.R. China.
Liquan
L
Hong
Cancer Institute, Zhejiang University, Hangzhou, Zhejiang 310009, P.R. China.
Hang
H
Zhang
Department of Laboratory Medicine, Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang 310015, P.R. China.
Feng
F
Pan
Department of Laboratory Medicine, Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang 310015, P.R. China.
Yuhua
Y
Liu
Department of Pathology, City of Hope National Medical Center, Duarte, CA 91010, USA.
Peiguo
P
Chu
Sino-American Cancer Foundation, Temple City, CA 91780, USA.
Shu
S
Zheng
Department of Laboratory Medicine, Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang 310015, P.R. China.
Guoqiang
G
Lou
Taipei Medical University, Taipei 110, Taiwan, R.O.C.
Yun
Y
Yen
D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000096:biosynthesis* / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D047628:Estrogen Receptor alpha / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D012696:Glycine Hydroxymethyltransferase / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D008875:Middle Aged; D008928:Mitochondria / Q000235:genetics; D009367:Neoplasm Staging; D011379:Prognosis
D014408:Biomarkers, Tumor; D047628:Estrogen Receptor alpha; D012696:Glycine Hydroxymethyltransferase; C520541:SHMT protein, human
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