title: Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies.
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.
authors.affiliation: Department of Biochemistry, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Lehmann
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Bauer
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.forename: Melinda E
authors.initials: ME
authors.lastname: Sanders
authors.forename: A Bapsi
authors.initials: AB
authors.lastname: Chakravarthy
authors.forename: Yu
authors.initials: Y
authors.lastname: Shyr
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Pietenpol
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000145:classification / Q000188:drug therapy* / Q000235:genetics* / Q000503:physiopathology; D045744:Cell Line, Tumor; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D051379:Mice; D008819:Mice, Nude; D010641:Phenotype; D015398:Signal Transduction / Q000502:physiology; D014183:Transplantation, Heterologous
chemical_list: D000970:Antineoplastic Agents