Aggressive triple negative breast cancers have unique molecular signature on the basis of mitochondrial genetic and functional defects

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1864

Article

Guha, Manti¹  Srinivasan, Satish¹  Raman, Pichai^2,7  Jiang, Yuefu³  Kaufman, Brett A.³  Taylor, Deanne²  Dong, Dawei¹  Chakrabarti, Rumela¹  Picard, Martin⁶  Carstens, Russ P.⁵  Kijima, Yuko⁴  Feldman, Mike⁵  Avadhani, Narayan G.¹ 

[1] Univ Penn, Sch Vet Med, Dept Biomed Sci, 3800 Spruce St, Philadelphia, PA 19104 USA

[2] Childrens Hosp Philadelphia, Dept Biomed & Hlth Informat, Philadelphia, PA 19104 USA

[3] Univ Pittsburgh, Ctr Metab & Mitochondrial Med, Dept Med, Div Cardiol, Pittsburgh, PA USA

[4] Kagoshima Univ, Dept Digest Breast & Thyroid Surg, 8-35-1 Sakuragaoka, Kagoshima 8908544, Japan

[5] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA

[6] Columbia Univ, Med Ctr, Dept Psychiat, Div Behav Med, New York, NY USA

[7] Childrens Hosp Philadelphia, Ctr Mitochondrial & Epigen Med, Philadelphia, PA 19104 USA

关键词: Mitochondrial DNA copy number;    Mitochondrial DNA sequence imbalance;    Metabolic gene expression;    Triple negative breast cancer;    ESRP1;   

DOI  :  10.1016/j.bbadis.2018.01.002

来源: Elsevier

【 摘 要 】

Metastatic breast cancer is a leading cause of cancer-related deaths in women worldwide. Patients with triple negative breast cancer (TNBCs), a highly aggressive tumor subtype, have a particularly poor prognosis. Multiple reports demonstrate that altered content of the multicopy mitochondria] genome (mtDNA) in primary breast tumors correlates with poor prognosis. We earlier reported that mtDNA copy number reduction in breast cancer cell lines induces an epithelial-mesenchymal transition associated with metastasis. However, it is unknown whether the breast tumor subtypes (TNBC, Luminal and HER2 +) differ in the nature and amount of mitochondrial defects and if mitochondrial defects can be used as a marker to identify tumors at risk for metastasis. By analyzing human primary tumors, cell lines and the TCGA dataset, we demonstrate a high degree of variability in mitochondrial defects among the tumor subtypes and TNBCs, in particular, exhibit higher frequency of mitochondrial defects, including reduced mtDNA content, mtDNA sequence imbalance (mtRNR1:ND4), impaired mitochondrial respiration and metabolic switch to glycolysis which is associated with tumorigenicity. We identified that genes involved in maintenance of mitochondrial structural and functional integrity are differentially expressed in TNBCs compared to non-TNBC tumors. Furthermore, we identified a subset of TNBC tumors that contain lower expression of epithelial splicing regulatory protein (ESRP)-1, typical of metastasizing cells. The overall impact of our findings reported here is that mitochondrial heterogeneity among TNBCs can be used to identify TNBC patients at risk of metastasis and the altered metabolism and metabolic genes can be targeted to improve chemotherapeutic response.

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