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.

KR-33028, a potent inhibitor of the Na+/H+ exchanger NHE1, suppresses metastatic potential of triple-negative breast cancer cells

“…We tested KR-33028 on three different TNBC cell models: highly invasive, [24]. To confirm that effects of KR-33028 were specific to inhibition of NHE1, we also studied its effect on MDA-MB-231 cells where NHE1 was knocked out (231koNHE1).…”

Recent trends in microRNA research into breast cancer with particular focus on the associations between microRNAs and intrinsic subtypes

“…The LAR subtype is associated with high androgen receptor (AR) expression levels. 94,95 The miRNA expression profiles of these molecular subtypes of TNBC might differ.…”

Friend leukemia virus integration 1 is a predictor of poor prognosis of breast cancer and promotes metastasis and cancer stem cell properties of breast cancer cells

“…FLI‐1 can activate RhoA and Rac1, which correlates with breast cancer metastasis 15. The MDA‐MB231 cell line with a high expression of FLI‐1 has already been proved to possess mesenchymal properties and exhibit high expression of EMT‐associated genes 21, 22. These findings indicate that FLI‐1 might be related to the EMT program in the MDA‐MB231 cells.…”

“…The latter is a luminal A type breast cancer cell line, and the former has been the most widely accepted TNBC subtype with mesenchymal properties 21, 22. Studies have demonstrated that tumor cells can eventually enter the invasion‐metastasis cascade, a prerequisite is the acquisition of mesenchymal properties—epithelial‐mesenchymal transition (EMT) 4, 23.…”