Cancer stem cell markers in breast cancer: pathological, clinical and prognostic significance - PubMed (original) (raw)

Cancer stem cell markers in breast cancer: pathological, clinical and prognostic significance

H Raza Ali et al. Breast Cancer Res. 2011.

Abstract

Introduction: The 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).

Methods: We 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.

Results: In 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).

Conclusions: Breast 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.

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Figures

Figure 1

Figure 1

Photomicrographs of CSC marker expression in normal breast tissue. A. Double immunostaining for CD44 (red) and CD24 (brown) reveals membranous CD44 expression of myoepithelial cells and some luminal cells. CD24 stains luminal apical membranes and secretions. B. IHC for ALDH1A1 showed different patterns, including staining of single luminal cells (right panel), of whole lobules (left panel) and stromal cells. C. IHC for ALDH1A3 (left panel) shows weak cytoplasmic of most epithelial and mesenchymal cells. IHC for ITGA6 (right panel) shows membranous staining of both myoepithelial and luminal cells.

Figure 2

Figure 2

Photomicrographs of CSC marker expression in invasive breast carcinoma. A. Membranous CD44 (red) staining and cytoplasmic CD24 (brown) staining of carcinoma cells. Tumours contained different proportions of positive cells, including cases dominated by CD44+CD24-/low cells (left panel) and others composed of CD24 expressing cells exclusively (right panel). B. Examples of low (left panel) and high (right panel) ALDH1A1 expression. C. Examples of high ALDH1A3 (left panel) and high ITGA6 (right panel) expression.

Figure 3

Figure 3

Heatmap of CSC marker expression across breast cancer molecular subtypes. Heatmap illustrating the unclustered distribution of cases from a single randomly selected imputed dataset across molecular subtypes defined by a five-marker IHC classifier. CSC markers arranged by average linkage clustering.

Figure 4

Figure 4

Kaplan-Meier survival plots of ITGA6 and Total CSC expression in ER- cases for BCSS. A. ITGA6 expression as a dichotomised variable (zero- to two-year follow-up, log-rank P = 0.0016; n (events): ITGA6- = 309 (14), ITGA6+ = 52 (8)). B. Total CSC composite score (zero- to four-year follow-up, log-rank P = 0.0173; n (events): CSC 0 = 164 (25), CSC 1 = 84 (22), CSC 2 = 19 (5), CSC 3 to 4 = 7 (4)).

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