Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies

Brian D. Lehmann, Joshua A. Bauer, Xi Chen, Melinda E. Sanders, A. Bapsi Chakravarthy, Yu Shyr, Jennifer A. Pietenpol

Research output: Contribution to journalArticle

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Abstract

Triple-negative breast cancer (TNBC) is a highly diverse group of cancers, and subtyping is necessary to better identify molecular-based therapies. In this study, we analyzed gene expression (GE) profiles from 21 breast cancer data sets and identified 587 TNBC cases. Cluster analysis identified 6 TNBC subtypes displaying unique GE and ontologies, including 2 basal-like (BL1 and BL2), an immunomodulatory (IM), a mesenchymal (M), a mesenchymal stem - like (MSL), and a luminal androgen receptor (LAR) subtype. Further, GE analysis allowed us to identify TNBC cell line models representative of these subtypes. Predicted "driver" signaling pathways were pharmacologically targeted in these cell line models as proof of concept that analysis of distinct GE signatures can inform therapy selection. BL1 and BL2 subtypes had higher expression of cell cycle and DNA damage response genes, and representative cell lines preferentially responded to cisplatin. M and MSL subtypes were enriched in GE for epithelial-mesenchymal transition, and growth factor pathways and cell models responded to NVP-BEZ235 (a PI3K/mTOR inhibitor) and dasatinib (an abl/src inhibitor). The LAR subtype includes patients with decreased relapse-free survival and was characterized by androgen receptor (AR) signaling. LAR cell lines were uniquely sensitive to bicalutamide (an AR antagonist). These data may be useful in biomarker selection, drug discovery, and clinical trial design that will enable alignment of TNBC patients to appropriate targeted therapies.

Original languageEnglish (US)
Pages (from-to)2750-2767
Number of pages18
JournalJournal of Clinical Investigation
Volume121
Issue number7
DOIs
StatePublished - Jul 1 2011
Externally publishedYes

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Triple Negative Breast Neoplasms
Forensic Anthropology
Androgen Receptors
Cell Line
Transcriptome
Gene Expression
Androgen Receptor Antagonists
Therapeutics
Gene Ontology
Epithelial-Mesenchymal Transition
Drug Discovery
Phosphatidylinositol 3-Kinases
Cisplatin
DNA Damage
Cluster Analysis
Intercellular Signaling Peptides and Proteins
Cell Cycle
Biomarkers
Clinical Trials
Breast Neoplasms

ASJC Scopus subject areas

  • Medicine(all)

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Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. / Lehmann, Brian D.; Bauer, Joshua A.; Chen, Xi; Sanders, Melinda E.; Chakravarthy, A. Bapsi; Shyr, Yu; Pietenpol, Jennifer A.

In: Journal of Clinical Investigation, Vol. 121, No. 7, 01.07.2011, p. 2750-2767.

Research output: Contribution to journalArticle

Lehmann, Brian D. ; Bauer, Joshua A. ; Chen, Xi ; Sanders, Melinda E. ; Chakravarthy, A. Bapsi ; Shyr, Yu ; Pietenpol, Jennifer A. / Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. In: Journal of Clinical Investigation. 2011 ; Vol. 121, No. 7. pp. 2750-2767.
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