title: Characterizing the heterogeneity of triple-negative breast cancers using microdissected normal ductal epithelium and RNA-sequencing.
abstract: Triple-negative breast cancers (TNBCs) are a heterogeneous set of tumors defined by an absence of actionable therapeutic targets (ER, PR, and HER-2). Microdissected normal ductal epithelium from healthy volunteers represents a novel comparator to reveal insights into TNBC heterogeneity and to inform drug development. Using RNA-sequencing data from our institution and The Cancer Genome Atlas (TCGA) we compared the transcriptomes of 94 TNBCs, 20 microdissected normal breast tissues from healthy volunteers from the Susan G. Komen for the Cure Tissue Bank, and 10 histologically normal tissues adjacent to tumor. Pathway analysis comparing TNBCs to optimized normal controls of microdissected normal epithelium versus classic controls composed of adjacent normal tissue revealed distinct molecular signatures. Differential gene expression of TNBC compared with normal comparators demonstrated important findings for TNBC-specific clinical trials testing targeted agents; lack of over-expression for negative studies and over-expression in studies with drug activity. Next, by comparing each individual TNBC to the set of microdissected normals, we demonstrate that TNBC heterogeneity is attributable to transcriptional chaos, is associated with non-silent DNA mutational load, and explains transcriptional heterogeneity in addition to known molecular subtypes. Finally, chaos analysis identified 146 core genes dysregulated in >90 % of TNBCs revealing an over-expressed central network. In conclusion, use of microdissected normal ductal epithelium from healthy volunteers enables an optimized approach for studying TNBC and uncovers biological heterogeneity mediated by transcriptional chaos.
authors.affiliation: Division of General Surgery, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA, mradovic@iupui.edu.
authors.forename: Milan
authors.initials: M
authors.lastname: Radovich
authors.forename: Susan E
authors.initials: SE
authors.lastname: Clare
authors.forename: Rutuja
authors.initials: R
authors.lastname: Atale
authors.forename: Ivanesa
authors.initials: I
authors.lastname: Pardo
authors.forename: Bradley A
authors.initials: BA
authors.lastname: Hancock
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Solzak
authors.forename: Nawal
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authors.lastname: Kassem
authors.forename: Theresa
authors.initials: T
authors.lastname: Mathieson
authors.forename: Anna Maria V
authors.initials: AM
authors.lastname: Storniolo
authors.forename: Connie
authors.initials: C
authors.lastname: Rufenbarger
authors.forename: Heather A
authors.initials: HA
authors.lastname: Lillemoe
authors.forename: Rachel J
authors.initials: RJ
authors.lastname: Blosser
authors.forename: Mi Ran
authors.initials: MR
authors.lastname: Choi
authors.forename: Candice A
authors.initials: CA
authors.lastname: Sauder
authors.forename: Diane
authors.initials: D
authors.lastname: Doxey
authors.forename: Jill E
authors.initials: JE
authors.lastname: Henry
authors.forename: Eric E
authors.initials: EE
authors.lastname: Hilligoss
authors.forename: Onur
authors.initials: O
authors.lastname: Sakarya
authors.forename: Fiona C
authors.initials: FC
authors.lastname: Hyland
authors.forename: Matthew
authors.initials: M
authors.lastname: Hickenbotham
authors.forename: Jin
authors.initials: J
authors.lastname: Zhu
authors.forename: Jarret
authors.initials: J
authors.lastname: Glasscock
authors.forename: Sunil
authors.initials: S
authors.lastname: Badve
authors.forename: Mircea
authors.initials: M
authors.lastname: Ivan
authors.forename: Yunlong
authors.initials: Y
authors.lastname: Liu
authors.forename: George W
authors.initials: GW
authors.lastname: Sledge
authors.forename: Bryan P
authors.initials: BP
authors.lastname: Schneider
mesh_terms: D016022:Case-Control Studies; D016000:Cluster Analysis; D005260:Female; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D006801:Humans; D042361:Mammary Glands, Human / Q000378:metabolism; D042282:Microdissection; D009154:Mutation; D017423:Sequence Analysis, RNA; D014158:Transcription, Genetic; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*
chemical_list: C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors