Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies
Brian D. Lehmann, … , Yu Shyr, Jennifer A. Pietenpol
Brian D. Lehmann, … , Yu Shyr, Jennifer A. Pietenpol
Published June 1, 2011
Citation Information: J Clin Invest. 2011;121(7):2750-2767. https://doi.org/10.1172/JCI45014.
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Research Article

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

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

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Figure 4

Basal-like TNBC subtypes have differential sensitivity to DNA-damaging agents.

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Basal-like TNBC subtypes have differential sensitivity to DNA-damaging a...
IC50 values for TNBC cell lines treated with PARP inhibitors (A) veliparib, (C) olaparib, or (E) cisplatin for 72 hours. Error bars reflect SEM for 3 independent experiments. Black horizontal lines above various bars in the plots indicate cell lines that failed to achieve an IC50 at the highest dose of veliparib (30 μM), olaparib (100 μM), or cisplatin (30 μM). Cell lines that carry BRCA1 or BRCA2 mutations (pink) are displayed below the graph. Dot plot shows the log distribution of drug sensitivity to PARP inhibitors (B) veliparib, (D) olaparib, or (F) cisplatin in the basal-like subtypes (BL = BL1 + BL2), the mesenchymal-like subtypes (ML = M + MSL), and the LAR subtype. Black horizontal bars in the dot plot indicate the mean IC50 for each of the subtypes. *Statistically significant differences in IC50 values of BL compared with ML (P = 0.017) and LAR (P = 0.032), as determined by Mann-Whitney U test.