title: Comprehensive transcriptome analysis identifies novel molecular subtypes and subtype-specific RNAs of triple-negative breast cancer.
abstract: BACKGROUND
  Triple-negative breast cancer (TNBC) is a highly heterogeneous group of cancers, and molecular subtyping is necessary to better identify molecular-based therapies. While some classifiers have been established, no one has integrated the expression profiles of long noncoding RNAs (lncRNAs) into such subtyping criterions. Considering the emerging important role of lncRNAs in cellular processes, a novel classification integrating transcriptome profiles of both messenger RNA (mRNA) and lncRNA would help us better understand the heterogeneity of TNBC.
  
  
  METHODS
  Using human transcriptome microarrays, we analyzed the transcriptome profiles of 165 TNBC samples. We used k-means clustering and empirical cumulative distribution function to determine optimal number of TNBC subtypes. Gene Ontology (GO) and pathway analyses were applied to determine the main function of the subtype-specific genes and pathways. We conducted co-expression network analyses to identify interactions between mRNAs and lncRNAs.
  
  
  RESULTS
  All of the 165 TNBC tumors were classified into four distinct clusters, including an immunomodulatory subtype (IM), a luminal androgen receptor subtype (LAR), a mesenchymal-like subtype (MES) and a basal-like and immune suppressed (BLIS) subtype. The IM subtype had high expressions of immune cell signaling and cytokine signaling genes. The LAR subtype was characterized by androgen receptor signaling. The MES subtype was enriched with growth factor signaling pathways. The BLIS subtype was characterized by down-regulation of immune response genes, activation of cell cycle, and DNA repair. Patients in this subtype experienced worse recurrence-free survival than others (log rank test, P = 0.045). Subtype-specific lncRNAs were identified, and their possible biological functions were predicted using co-expression network analyses.
  
  
  CONCLUSIONS
  We developed a novel TNBC classification system integrating the expression profiles of both mRNAs and lncRNAs and determined subtype-specific lncRNAs that are potential biomarkers and targets. If further validated in a larger population, our novel classification system could facilitate patient counseling and individualize treatment of TNBC.
authors.affiliation: Department of Breast Surgery, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, P.R. China.|Cancer Institute, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, P.R. China.|Department of Oncology, Shanghai Medical College, Fudan University, 270 Dong-An Road, Shanghai, 200032, P.R. China.
authors.forename: Yi-Rong
authors.initials: YR
authors.lastname: Liu
authors.affiliation: Department of Breast Surgery, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, P.R. China.|Cancer Institute, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, P.R. China.|Department of Oncology, Shanghai Medical College, Fudan University, 270 Dong-An Road, Shanghai, 200032, P.R. China.
authors.forename: Yi-Zhou
authors.initials: YZ
authors.lastname: Jiang
authors.affiliation: Department of Breast Surgery, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, P.R. China.|Cancer Institute, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, P.R. China.|Department of Oncology, Shanghai Medical College, Fudan University, 270 Dong-An Road, Shanghai, 200032, P.R. China.
authors.forename: Xiao-En
authors.initials: XE
authors.lastname: Xu
authors.affiliation: Department of Breast Surgery, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, P.R. China.|Cancer Institute, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, P.R. China.|Department of Oncology, Shanghai Medical College, Fudan University, 270 Dong-An Road, Shanghai, 200032, P.R. China.
authors.forename: Ke-Da
authors.initials: KD
authors.lastname: Yu
authors.affiliation: Department of Breast Surgery, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, P.R. China.|Cancer Institute, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, P.R. China.|Department of Oncology, Shanghai Medical College, Fudan University, 270 Dong-An Road, Shanghai, 200032, P.R. China.
authors.forename: Xi
authors.initials: X
authors.lastname: Jin
authors.affiliation: Department of Breast Surgery, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, P.R. China.|Cancer Institute, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, P.R. China.|Department of Oncology, Shanghai Medical College, Fudan University, 270 Dong-An Road, Shanghai, 200032, P.R. China.
authors.forename: Xin
authors.initials: X
authors.lastname: Hu
authors.affiliation: Department of Breast Surgery, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, P.R. China.|Cancer Institute, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, P.R. China.|Department of Oncology, Shanghai Medical College, Fudan University, 270 Dong-An Road, Shanghai, 200032, P.R. China.
authors.forename: Wen-Jia
authors.initials: WJ
authors.lastname: Zuo
authors.affiliation: Department of Breast Surgery, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, P.R. China.|Cancer Institute, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, P.R. China.|Department of Oncology, Shanghai Medical College, Fudan University, 270 Dong-An Road, Shanghai, 200032, P.R. China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Hao
authors.affiliation: Department of Breast Surgery, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, P.R. China.|Cancer Institute, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, P.R. China.|Department of Oncology, Shanghai Medical College, Fudan University, 270 Dong-An Road, Shanghai, 200032, P.R. China.
authors.forename: Jiong
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Breast Surgery, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, P.R. China.|Cancer Institute, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, P.R. China.|Department of Oncology, Shanghai Medical College, Fudan University, 270 Dong-An Road, Shanghai, 200032, P.R. China.
authors.forename: Guang-Yu
authors.initials: GY
authors.lastname: Liu
authors.affiliation: Department of Breast Surgery, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, P.R. China.|Cancer Institute, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, P.R. China.|Department of Oncology, Shanghai Medical College, Fudan University, 270 Dong-An Road, Shanghai, 200032, P.R. China.
authors.forename: Gen-Hong
authors.initials: GH
authors.lastname: Di
authors.affiliation: Department of Breast Surgery, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, P.R. China.|Cancer Institute, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, P.R. China.|Department of Oncology, Shanghai Medical College, Fudan University, 270 Dong-An Road, Shanghai, 200032, P.R. China.|Institutes of Biomedical Sciences, Fudan University, Shanghai, P.R. China.
authors.forename: Da-Qiang
authors.initials: DQ
authors.lastname: Li
authors.affiliation: Department of Breast Surgery, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, P.R. China.|Cancer Institute, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, P.R. China.|Department of Oncology, Shanghai Medical College, Fudan University, 270 Dong-An Road, Shanghai, 200032, P.R. China.|Institutes of Biomedical Sciences, Fudan University, Shanghai, P.R. China.
authors.forename: Xiang-Huo
authors.initials: XH
authors.lastname: He
authors.affiliation: Department of Breast Surgery, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, P.R. China.|Cancer Institute, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, P.R. China.|Department of Oncology, Shanghai Medical College, Fudan University, 270 Dong-An Road, Shanghai, 200032, P.R. China.|Institutes of Biomedical Sciences, Fudan University, Shanghai, P.R. China.
authors.forename: Wei-Guo
authors.initials: WG
authors.lastname: Hu
authors.affiliation: Department of Breast Surgery, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, P.R. China. zhimingshao@yahoo.com.|Cancer Institute, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, P.R. China. zhimingshao@yahoo.com.|Department of Oncology, Shanghai Medical College, Fudan University, 270 Dong-An Road, Shanghai, 200032, P.R. China. zhimingshao@yahoo.com.|Institutes of Biomedical Sciences, Fudan University, Shanghai, P.R. China. zhimingshao@yahoo.com.
authors.forename: Zhi-Ming
authors.initials: ZM
authors.lastname: Shao
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000096:biosynthesis / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D018740:Genetic Heterogeneity; D006801:Humans; D046228:Microarray Analysis; D008875:Middle Aged; D062085:RNA, Long Noncoding / Q000096:biosynthesis / Q000235:genetics*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics*; D059467:Transcriptome / Q000235:genetics*; D064726:Triple Negative Breast Neoplasms / Q000145:classification / Q000235:genetics* / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor; D062085:RNA, Long Noncoding; D012333:RNA, Messenger
keywords: Long non-coding RNA; Messenger RNA; Molecular subtypes; Transcriptome analysis; Triple-negative breast cancer