Characterizing the heterogeneity of triple-negative breast cancers using microdissected normal ductal epithelium and RNA-sequencing

Milan Radovich, Susan E. Clare, Rutuja Atale, Ivanesa Pardo, Bradley A. Hancock, Jeffrey P. Solzak, Nawal Kassem, Theresa Mathieson, Anna Maria V. Storniolo, Connie Rufenbarger, Heather A. Lillemoe, Rachel J. Blosser, Mi Ran Choi, Candice Sauder, Diane Doxey, Jill E. Henry, Eric E. Hilligoss, Onur Sakarya, Fiona C. Hyland, Matthew HickenbothamJin Zhu, Jarret Glasscock, Sunil Badve, Mircea Ivan, Yunlong Liu, George W. Sledge, Bryan P. Schneider

Research output: Contribution to journalArticle

18 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)57-68
Number of pages12
JournalBreast Cancer Research and Treatment
Volume143
Issue number1
DOIs
StatePublished - Jan 1 2014
Externally publishedYes

Keywords

  • Adjacent normal
  • Ductal epithelium
  • Normal breast
  • RNA-seq
  • TCGA
  • Triple-negative breast cancer

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    Radovich, M., Clare, S. E., Atale, R., Pardo, I., Hancock, B. A., Solzak, J. P., Kassem, N., Mathieson, T., Storniolo, A. M. V., Rufenbarger, C., Lillemoe, H. A., Blosser, R. J., Choi, M. R., Sauder, C., Doxey, D., Henry, J. E., Hilligoss, E. E., Sakarya, O., Hyland, F. C., ... Schneider, B. P. (2014). Characterizing the heterogeneity of triple-negative breast cancers using microdissected normal ductal epithelium and RNA-sequencing. Breast Cancer Research and Treatment, 143(1), 57-68. https://doi.org/10.1007/s10549-013-2780-y