ADHFE1 is a breast cancer oncogene and induces metabolic reprogramming
Prachi Mishra, … , Nagireddy Putluri, Stefan Ambs
Prachi Mishra, … , Nagireddy Putluri, Stefan Ambs
Published November 27, 2017
Citation Information: J Clin Invest. 2018;128(1):323-340. https://doi.org/10.1172/JCI93815.
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Research Article Metabolism Oncology

ADHFE1 is a breast cancer oncogene and induces metabolic reprogramming

Abstract

Metabolic reprogramming in breast tumors is linked to increases in putative oncogenic metabolites that may contribute to malignant transformation. We previously showed that accumulation of the oncometabolite, 2-hydroxyglutarate (2HG), in breast tumors was associated with MYC signaling, but not with isocitrate dehydrogenase (IDH) mutations, suggesting a distinct mechanism for increased 2HG in breast cancer. Here, we determined that D-2HG is the predominant enantiomer in human breast tumors and show that the D-2HG–producing mitochondrial enzyme, alcohol dehydrogenase, iron-containing protein 1 (ADHFE1), is a breast cancer oncogene that decreases patient survival. We found that MYC upregulates ADHFE1 through changes in iron metabolism while coexpression of both ADHFE1 and MYC strongly enhanced orthotopic tumor growth in MCF7 cells. Moreover, ADHFE1 promoted metabolic reprogramming with increased formation of D-2HG and reactive oxygen, a reductive glutamine metabolism, and modifications of the epigenetic landscape, leading to cellular dedifferentiation, enhanced mesenchymal transition, and phenocopying alterations that occur with high D-2HG levels in cancer cells with IDH mutations. Together, our data support the hypothesis that ADHFE1 and MYC signaling contribute to D-2HG accumulation in breast tumors and show that D-2HG is an oncogenic metabolite and potential driver of disease progression.

Authors

Prachi Mishra, Wei Tang, Vasanta Putluri, Tiffany H. Dorsey, Feng Jin, Fang Wang, Donewei Zhu, Lauren Amable, Tao Deng, Shaofei Zhang, J. Keith Killian, Yonghong Wang, Tsion Z. Minas, Harry G. Yfantis, Dong H. Lee, Arun Sreekumar, Michael Bustin, Wei Liu, Nagireddy Putluri, Stefan Ambs

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Figure 7

Reduced E-cadherin in tumors with high ADHFE1 and presence of an EMT signature in TCGA breast tumors with ADHFE1 amplifications.

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Reduced E-cadherin in tumors with high ADHFE1 and presence of an EMT sig...
(A) Evaluation of ADHFE1 and E-cadherin expression in 116 human breast tumors using immunohistochemistry. Tumors with high ADHFE1 expression (n = 35) were significantly more likely to show low E-cadherin expression (34.2%) than tumors with low ADHFE1 expression (13.5%). P = 0.02, Fisher’s exact test. (B) Differentially expressed genes between breast tumors with and without ADHFE1 amplifications (reference) were enriched for an EMT signature. The GSEA enrichment score was high (0.7) for upregulated EMT signature genes (black bars) in tumors with amplifications. FDR < 0.001. Forty-five breast tumors in the TCGA database had an ADHFE1 amplification. (C) Immunohistochemistry with representative ADHFE1 expression in a breast tumor. ADHFE1 is seen in the cytoplasm of the tumor epithelium (brown chromogen) and has a granular distribution, consistent with the mitochondrial location of the enzyme. (D) Representative E-cadherin expression in a breast tumor. Shown is staining of the cell membrane that is typical for this protein. Original magnification, ×400 (C and D).