These studies provide clinical evidence for a subpopulation of chemotherapy-resistant breast cancer-initiating cells. Lapatinib did not lead to an increase in these tumorigenic cells, and, in combination with conventional therapy, specific pathway inhibitors may provide a therapeutic strategy for eliminating these cells to decrease recurrence and improve long-term survival.
SummaryPrevious studies have suggested that breast cancer stem cells (BCSCs) mediate metastasis, are resistant to radiation and chemotherapy, and contribute to relapse. Although several BCSC markers have been described, it is unclear whether these markers identify the same or independent BCSCs. Here, we show that BCSCs exist in distinct mesenchymal-like (epithelial-mesenchymal transition [EMT]) and epithelial-like (mesenchymal-epithelial transition [MET]) states. Mesenchymal-like BCSCs characterized as CD24−CD44+ are primarily quiescent and localized at the tumor invasive front, whereas epithelial-like BCSCs express aldehyde dehydrogenase (ALDH), are proliferative, and are located more centrally. The gene-expression profiles of mesenchymal-like and epithelial-like BCSCs are remarkably similar across different molecular subtypes of breast cancer, and resemble those of distinct basal and luminal stem cells found in the normal breast. We propose that the plasticity of BCSCs that allows them to transition between EMT- and MET-like states endows these cells with the capacity for tissue invasion, dissemination, and growth at metastatic sites.
Purpose
Genomic profiling studies suggest triple-negative breast cancer (TNBC) is a heterogeneous disease. In this study we sought to define TNBC subtypes and identify subtype-specific markers and targets.
Patients and Methods
RNA and DNA profiling analyses were conducted on 198 TNBC tumors (ER-negativity defined as Allred Scale value ≤2) with >50% cellularity (discovery set: n=84; validation set: n=114) collected at Baylor College of Medicine. An external data set of 7 publically-accessible TNBC studies was used to confirm results. DNA copy number, disease-free survival (DFS) and disease-specific survival (DSS) were analyzed independently using these datasets.
Results
We identified and confirmed four distinct TNBC subtypes: (1) Luminal-AR (LAR); 2) Mesenchymal (MES); 3) Basal-Like Immune-Suppressed (BLIS), and 4) Basal-Like Immune-Activated (BLIA). Of these, prognosis is worst for BLIS tumors and best for BLIA tumors for both DFS (logrank test p=0.042 and 0.041, respectively) and DSS (logrank test p=0.039 and 0.029, respectively). DNA copy number analysis produced two major groups (LAR and MES/BLIS/BLIA), and suggested gene amplification drives gene expression in some cases (FGFR2 (BLIS)). Putative subtype-specific targets were identified: 1) LAR: androgen receptor and the cell surface mucin MUC1; 2) MES: growth factor receptors (PDGF receptor A; c-Kit); 3) BLIS: an immune suppressing molecule (VTCN1); and 4) BLIA: Stat signal transduction molecules and cytokines.
Conclusion
There are four stable TNBC subtypes characterized by the expression of distinct molecular profiles that have distinct prognoses. These studies identify novel subtype-specific targets that can be targeted in the future for effective treatment of TNBCs.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.