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

TLDR

Triple‑negative breast cancer is a highly heterogeneous disease, and subtyping is essential to identify molecular‑based therapies. The study aimed to classify TNBC into distinct subtypes and develop representative preclinical models to guide targeted therapy selection. Gene‑expression profiling of 21 breast‑cancer datasets identified 587 TNBC cases, which were clustered into six subtypes, and predicted driver pathways were pharmacologically targeted in corresponding cell‑line models. Six subtypes were defined, each with unique gene‑expression signatures and therapeutic sensitivities—BL1/BL2 to cisplatin, M/ MSL to PI3K/mTOR and Src inhibitors, and LAR to the AR antagonist bicalutamide—offering a biomarker‑driven framework for therapy selection.

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.