2. Academic Validation
  3. Metabolic-Pathway-Based Subtyping of Triple-Negative Breast Cancer Reveals Potential Therapeutic Targets

Metabolic-Pathway-Based Subtyping of Triple-Negative Breast Cancer Reveals Potential Therapeutic Targets

  • Cell Metab. 2021 Jan 5;33(1):51-64.e9. doi: 10.1016/j.cmet.2020.10.012.
Yue Gong 1,  Peng Ji 1,  Yun-Song Yang 1,  Shao Xie 2,  Tian-Jian Yu 1,  Yi Xiao 1,  Ming-Liang Jin 1,  Ding Ma 1,  Lin-Wei Guo 1,  Yu-Chen Pei 3,  Wen-Jun Chai 4,  Da-Qiang Li 5,  Fan Bai 6,  François Bertucci 7,  Xin Hu 8,  Yi-Zhou Jiang 9,  Zhi-Ming Shao 10
Affiliations

Affiliations

  • 1 Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China.
  • 2 Institute of Pediatrics, Children's Hospital, Fudan University, Shanghai 201102, P.R. China.
  • 3 Precision Cancer Medicine Center, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China.
  • 4 Laboratory Animal Center, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China.
  • 5 Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China; Precision Cancer Medicine Center, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China.
  • 6 Biomedical Pioneering Innovation Center (BIOPIC), School of Life Sciences, Peking University, Beijing 100871, P.R. China.
  • 7 Predictive Oncology Laboratory and Department of Medical Oncology, CRCM, Institut Paoli-Calmettes, INSERM, CNRS, Aix-Marseille Université, Marseille, France.
  • 8 Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China; Precision Cancer Medicine Center, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China. Electronic address: xinhu@fudan.edu.cn.
  • 9 Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China; Precision Cancer Medicine Center, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China. Electronic address: yizhoujiang@fudan.edu.cn.
  • 10 Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China; Precision Cancer Medicine Center, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China. Electronic address: zhimingshao@yahoo.com.
PMID: 33181091 DOI: 10.1016/j.cmet.2020.10.012
Abstract

Triple-negative breast Cancer (TNBC) remains an unmet medical challenge. We investigated metabolic dysregulation in TNBCs by using our multi-omics database (n = 465, the largest to date). TNBC samples were classified into three heterogeneous metabolic-pathway-based subtypes (MPSs) with distinct metabolic features: Mps1, the lipogenic subtype with upregulated lipid metabolism; MPS2, the glycolytic subtype with upregulated carbohydrate and nucleotide metabolism; and MPS3, the mixed subtype with partial pathway dysregulation. These subtypes were validated by metabolomic profiling of 72 samples. These three subtypes had distinct prognoses, molecular subtype distributions, and genomic alterations. Moreover, Mps1 TNBCs were more sensitive to metabolic inhibitors targeting fatty acid synthesis, whereas MPS2 TNBCs showed higher sensitivity to inhibitors targeting glycolysis. Importantly, inhibition of Lactate Dehydrogenase could enhance tumor response to anti-PD-1 immunotherapy in MPS2 TNBCs. Collectively, our analysis demonstrated the metabolic heterogeneity of TNBCs and enabled the development of personalized therapies targeting unique tumor metabolic profiles.

Keywords

glycolysis; heterogeneity; immunotherapy; metabolic inhibitor; metabolic pathway; metabolism; subtype; survival; triple-negative breast cancer.

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