Abstract
IntroductionThe cancer stem cell (CSC) hypothesis states that tumours consist of a cellular hierarchy with CSCs at the apex driving tumour recurrence and metastasis. Hence, CSCs are potentially of profound clinical importance. We set out to establish the clinical relevance of breast CSC markers by profiling a large cohort of breast tumours in tissue microarrays (TMAs) using immunohistochemistry (IHC).MethodsWe included 4, 125 patients enrolled in the SEARCH population-based study with tumours represented in TMAs and classified into molecular subtype according to a validated IHC-based five-marker scheme. IHC was used to detect CD44/CD24, ALDH1A1, aldehyde dehydrogenase family 1 member A3 (ALDH1A3) and integrin alpha-6 (ITGA6). A 'Total CSC' score representing expression of all four CSC markers was also investigated. Association with breast cancer specific survival (BCSS) at 10 years was assessed using a Cox proportional-hazards model. This study was complied with REMARK criteria.ResultsIn ER negative cases, multivariate analysis showed that ITGA6 was an independent prognostic factor with a time-dependent effect restricted to the first two years of follow-up (hazard ratio (HR) for 0 to 2 years follow-up, 2.4; 95% confidence interval (95% CI), 1.2 to 4.8; P = 0.009). The composite 'Total CSC' score carried independent prognostic significance in ER negative cases for the first four years of follow-up (HR for 0 to 4 years follow-up, 1.3; 95% CI, 1.1 to 1.6; P = 0.006).ConclusionsBreast CSC markers do not identify identical subpopulations in primary tumours. Both ITGA6 and a composite Total CSC score show independent prognostic significance in ER negative disease. The use of multiple markers to identify tumours enriched for CSCs has the greatest prognostic value. In the absence of more specific markers, we propose that the effective translation of the CSC hypothesis into patient benefit will necessitate the use of a panel of markers to robustly identify tumours enriched for CSCs.
Highlights
The cancer stem cell (CSC) hypothesis states that tumours consist of a cellular hierarchy with cancer stem cells (CSCs) at the apex driving tumour recurrence and metastasis
In keeping with the observations of Ginestier et al [3], strong aldehyde dehydrogenase family 1 member A1 (ALDH1A1) expression was seen in isolated luminal cells in terminal-ductal lobular units (TDLUs)
We have attempted to establish the clinical relevance of CSCs in breast cancer by using IHC to assay for putative CSC markers in a large cohort of primary breast tumours in tissue microarray (TMA)
Summary
The cancer stem cell (CSC) hypothesis states that tumours consist of a cellular hierarchy with CSCs at the apex driving tumour recurrence and metastasis. The existence of tumour initiating cells called cancer stem cells (CSCs) in breast cancer has been demonstrated by several studies [1,2,3]. It has been shown that xenotransplanted cell subpopulations enriched for CSCs can generate tumours in non-obese severe-combined immunodeficient (NOD/SCID) mice from a fraction of the number of unselected cells required to form tumours. Tumours resulting from the implantation of small numbers of CSCs recapitulate the molecular heterogeneity of the original mixed. After excluding nonepithelial cells (lineage-), CD44+CD24-/low cells were enriched by flow cytometry and subsequently implanted into NOD/SCID mice. The CD44+CD24-/low cells were able to form tumours in NOD/SCID mice from fewer cells than the mixed population with 10- to 50-fold enrichment for this ability. The resulting xenografts were found to exhibit the same phenotypic diversity as the original tumours [1]
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