Abstract
Breast cancer is a heterogenous disease, composed of tumour cells with differing gene expressions and phenotypes. Very few antigens have been identified and a better understanding of tumour initiating-cells as targets for therapy is critically needed. Recently, a rare subpopulation of cells within tumours has been described with the ability to: (i) initiate and sustain tumour growth; (ii) resist traditional therapies and allow for secondary tumour dissemination; and (iii) display some of the characteristics of stem cells such as self-renewal. These cells are termed tumour-initiating cells or cancer stem cells, or alternatively, in the case of breast cancer, breast cancer stem cells. Previous studies have demonstrated that breast cancer stem cells can be enriched for in “tumoursphere” culture. Proteomics represents a novel way to investigate protein expression between cells. We hypothesise that characterisation of the proteome of the breast cancer line MCF-7 tumourspheres compared to adherent/differentiated cells identifies proteins of novel interest for further isolating or targeting breast cancer stem cells. We present evidence that: (i) the proteome of adherent cells is different to the proteome of cells grown in sphere medium from either early passage (passage 2) or late passage (passage 5) spheres; (ii) that spheres are enriched in expression of a variety of tumour-relevant proteins (including MUC1 and Galectin-3); and (iii) that targeting of one of these identified proteins (galectin-3) using an inhibitor (N-acetyllactosamine) decreases sphere formation/self-renewal of MCF-7 cancer stem cells in vitro and tumourigenicity in vivo. Hence, proteomic analysis of tumourspheres may find use in identifying novel targets for future therapy. The therapeutic targeting of breast cancer stem cells, a highly clinically relevant sub-population of tumour cells, has the potential to eliminate residual disease and may become an important component of a multi-modality treatment of cancer.
Highlights
Breast cancer accounts for 18% of all female cancers [1]
Application of the neurosphere assay culture conditions have been used to identify undifferentiated human mammary stem cell grown in culture [6] known as ‘‘mammospheres’’ and to identify candidate human breast cancer stem cells (BCSCs) in breast cancer cell lines [7] known as ‘‘tumourspheres.’’ Sphere culture systems have shown that tumourspheres cultured from human breast cancer cell lines exhibit stem cell-like functional properties such as symmetric division and self-renewal [8] and a variety of phenotypic properties, such as HER2 [9,10], CD49f [11], protein phosphatase and tensin homolog – PTEN [12], EpCAM [13,14], mucin 1( MUC1) [15], CD44+/CD242/low populations [13,14], and aldehyde dehydrogenase 1 – ALDH1 [16,17] amongst others
Results from our group have shown that MCF-7 spheres have a positive symmetric division rate of cancer stem cells [8] and that spheres are more tumourigenic than matched adherent cells [18]
Summary
Breast cancer accounts for 18% of all female cancers [1]. As such, development of models to investigate breast cancer for treatment or prevention is a major focus of scientific research. Prominent in the breast cancer field has been the notion of the existence of a transformed population of cells with many of the properties of stem cells (self-renewal, differentiation, long-term culture capacity) that may be responsible for the heterogeneity, origin and maintenance of tumours [2,3]. These stem cell-like cells designated as breast cancer stem cells (BCSCs) or alternatively as tumour-initiating cells, represent a minor subset of cells in the tumour and are distinct from more differentiated cells. The proteome of MCF-7 tumourspheres has yet to be defined
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