Mammosphere-derived gene set predicts outcome in patients with ER-positive breast cancer.

Abstract

Tumourigenic subpopulations with stem cell-like features have been identified in breast tumours and breast cancer cell lines. The hormone receptor status, molecular characteristics and clinical significance of these cells are still matters of debate. Enrichment for tumourigenic cells without the requirement of surface markers can be achieved by the in vitro mammosphere culture assay. Here we compared the hormone receptor status and genome-wide gene expression profiles of mammospheres derived from four oestrogen-receptor (ER) positive breast cancer cell lines with those of the respective parental cells. Immunohistochemistry and gene expression profiling revealed a significant reduction in the expression of progesterone receptor, proliferation and cell cycle regulated genes in mammospheres when compared to parental cell lines. The 200 most differentially expressed genes between mammospheres and parental cell lines were used to generate a 'mammosphere-derived' gene set. Hierarchical clustering of gene expression profiles of two independent cohorts of primary ER-positive cancers based on the 'mammosphere-derived' gene set revealed that the subgroup of breast cancers with profiles similar to those of mammospheres has a significantly longer overall survival. In conclusion, tumour-initiating breast cancer cells grown in mammospheres seem to reside in a quiescent state. ER-positive breast cancers with expression profiles similar to those of mammospheres have a better outcome, providing evidence in support of the concept that outcome of patients with ER-positive disease is for a large part determined by cell cycle and proliferation activity.