title: A shared transcriptional program in early breast neoplasias despite genetic and clinical distinctions.
abstract: BACKGROUND
  The earliest recognizable stages of breast neoplasia are lesions that represent a heterogeneous collection of epithelial proliferations currently classified based on morphology. Their role in the development of breast cancer is not well understood but insight into the critical events at this early stage will improve efforts in breast cancer detection and prevention. These microscopic lesions are technically difficult to study so very little is known about their molecular alterations.
  
  
  RESULTS
  To characterize the transcriptional changes of early breast neoplasia, we sequenced 3'- end enriched RNAseq libraries from formalin-fixed paraffin-embedded tissue of early neoplasia samples and matched normal breast and carcinoma samples from 25 patients. We find that gene expression patterns within early neoplasias are distinct from both normal and breast cancer patterns and identify a pattern of pro-oncogenic changes, including elevated transcription of ERBB2, FOXA1, and GATA3 at this early stage. We validate these findings on a second independent gene expression profile data set generated by whole transcriptome sequencing. Measurements of protein expression by immunohistochemistry on an independent set of early neoplasias confirms that ER pathway regulators FOXA1 and GATA3, as well as ER itself, are consistently upregulated at this early stage. The early neoplasia samples also demonstrate coordinated changes in long non-coding RNA expression and microenvironment stromal gene expression patterns.
  
  
  CONCLUSIONS
  This study is the first examination of global gene expression in early breast neoplasia, and the genes identified here represent candidate participants in the earliest molecular events in the development of breast cancer.
authors.forename: Alayne L
authors.initials: AL
authors.lastname: Brunner
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.forename: Xiangqian
authors.initials: X
authors.lastname: Guo
authors.forename: Robert T
authors.initials: RT
authors.lastname: Sweeney
authors.forename: Sushama
authors.initials: S
authors.lastname: Varma
authors.forename: Shirley X
authors.initials: SX
authors.lastname: Zhu
authors.forename: Rui
authors.initials: R
authors.lastname: Li
authors.forename: Robert
authors.initials: R
authors.lastname: Tibshirani
authors.forename: Robert B
authors.initials: RB
authors.lastname: West
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D005260:Female; D050990:GATA3 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods*; D015972:Gene Expression Regulation, Neoplastic; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D062085:RNA, Long Noncoding; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D011960:Receptors, Estrogen / Q000235:genetics* / Q000378:metabolism; D017423:Sequence Analysis, RNA / Q000379:methods; D059016:Tumor Microenvironment
chemical_list: D050990:GATA3 Transcription Factor; D051541:Hepatocyte Nuclear Factor 3-alpha; D062085:RNA, Long Noncoding; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; C496499:FOXA1 protein, human; C494749:GATA3 protein, human; C508053:ERBB2 protein, human