Gene signatures and potential therapeutic targets of amino acid metabolism in estrogen receptor-positive breast cancer

Chih-Yang Wang; Chung-Chieh Chiao; Nam Nhut Phan; Chung-Yen Li; Zheng-Da Sun; Jia-Zhen Jiang; Jui-Hsiang Hung; Yi-Ling Chen; Meng-Chi Yen; Tzu-Yang Weng; Wei-Ching Chen; Hui-Ping Hsu; Ming-Derg Lai

Gene signatures and potential therapeutic targets of amino acid metabolism in estrogen receptor-positive breast cancer

Am J Cancer Res. 2020 Jan 1;10(1):95-113. eCollection 2020.

Authors

Chih-Yang Wang^{1

2

3

4}, Chung-Chieh Chiao^{1

5}, Nam Nhut Phan⁶, Chung-Yen Li^{1

2}, Zheng-Da Sun⁷, Jia-Zhen Jiang⁸, Jui-Hsiang Hung⁹, Yi-Ling Chen¹⁰, Meng-Chi Yen¹¹, Tzu-Yang Weng^{1

2}, Wei-Ching Chen^{1

2}, Hui-Ping Hsu¹², Ming-Derg Lai^{1

2}

Affiliations

¹ Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University Tainan 70101, Taiwan.
² Institute of Basic Medical Sciences, National Cheng Kung University Tainan 70101, Taiwan.
³ Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University Taipei 11031, Taiwan.
⁴ Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University Taipei 11031, Taiwan.
⁵ School of Chinese Medicine for Post-Baccalaureate, I-Shou University Kaohsiung 82445, Taiwan.
⁶ NTT Institute of Hi-Technology, Nguyen Tat Thanh University Ho Chi Minh City, Vietnam.
⁷ Department of Radiology and Biomedical Imaging, University of California San Francisco, CA 94143, USA.
⁸ Emergency Department, Huashan Hospital North, Fudan University Shanghai 200040, China.
⁹ Department of Biotechnology, Chia Nan University of Pharmacy and Science Tainan 71710, Taiwan.
¹⁰ Department of Senior Citizen Service Management, Chia Nan University of Pharmacy and Science Tainan 71710, Taiwan.
¹¹ Department of Emergency Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University Kaohsiung 80708, Taiwan.
¹² Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University Tainan 70101, Taiwan.

PMID: 32064155
PMCID: PMC7017735

Abstract

Increased activity of amino acid transporters has been observed in a wide variety of cancers. However, whether amino acid metabolism is related to estrogen receptor-positive (ER⁺) breast cancer has been less well studied. We identified the rate-limiting enzyme involved in amino acid metabolism associated with ER⁺ breast cancer by integrating numerous bioinformatics tools and laboratory studies. The bioinformatics analysis revealed that highly expressed genes in ER⁺ breast cancer patients were correlated with breast cancer-related pathways, including ESR1 and PI3K signaling. The metabolic signaling and the amino acid metabolism were significantly regulated in breast neoplasms. We used the ER⁺ breast cancer cell line MCF-7 and breast cancer tissue from National Cheng Kung University Hospital to validate our findings in bioinformatics. In estradiol-treated MCF-7 cells, genes associated with anabolic metabolism of serine and methionine and genes associated with catabolic metabolism of tyrosine, phenylalanine and arginine were upregulated. Furthermore, the expression levels of ARG2, PSAT1, PSPH, TH, PAH, and MAT1A mRNA were increased in breast cancer patients relative to controls. The aforementioned genes were also found to be highly correlated with distant metastasis-free survival in breast cancer patients. High expression levels of ARG2, CBS, PHGDH, AHCY, HAL, TDO2, SHMT2, MAT1A, MAT2A, GLDC, GLS2, BCAT2, GLUD1, PAH and MTR contributed to poor prognoses, whereas high mRNA expression levels of HECA, CTH, PRODH, TAT, and MAT2B were correlated with good prognoses. FDA-approved drugs, including piperlongumine, ellipticine, etidronic acid, harmine, and meclozine, may have novel therapeutic effects in ER⁺ patients based on connectivity map (CMap) analyses. Collectively, our present study demonstrated that amino acid metabolism genes play crucial roles in tumor development and may serve as prospective drug targets or biomarkers for ER⁺ breast cancer.

Keywords: Breast cancer; amino acid metabolism; estrogen receptor.