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Transcriptional profiling of human breast cancer cell lines

ABSTRACT: In an experimental model of tumor dormancy, heat shock protein 27 (HSP27) was up-regulated in angiogenic human breast cancer cells when compared with non-angiogenic cells. Stable down-regulation of HSP27 in angiogenic tumor cells was followed by long-term tumor dormancy in vivo and associated with reduced intra-tumoral endothelial cell proliferation, decreased secretion of VEGF and bFGF from tumor cells, and increased expression of thrombospondin-1. Phosphorylation of the transcription factor STAT3 and nuclear expression of NFκB were reduced following suppression of HSP27. In contrast, tumor cell proliferation and apoptosis were not affected. By clinical validation, high HSP27 expression was associated with markers of aggressive tumors and decreased survival in breast cancer and melanoma patients. Our present findings suggest a link between HSP27 and dormancy through tumor-vascular interactions. Targeting HSP27, a multifunctional cytoprotective protein, might offer a novel strategy in cancer treatment.

ORGANISM(S): Homo sapiens

SUBMITTER: Straume O

PROVIDER: S-ECPF-TABM-883 | biostudies-other | 2012 May

REPOSITORIES: biostudies-other

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Project description:BackgroundTo improve cancer therapy, it is critical to target metastasizing cells. Circulating tumor cells (CTCs) are rare cells found in the blood of patients with solid tumors and may play a key role in cancer dissemination. Uncovering CTC phenotypes offers a potential avenue to inform treatment. However, CTC transcriptional profiling is limited by leukocyte contamination; an approach to surmount this problem is single cell analysis. Here we demonstrate feasibility of performing high dimensional single CTC profiling, providing early insight into CTC heterogeneity and allowing comparisons to breast cancer cell lines widely used for drug discovery.Methodology/principal findingsWe purified CTCs using the MagSweeper, an immunomagnetic enrichment device that isolates live tumor cells from unfractionated blood. CTCs that met stringent criteria for further analysis were obtained from 70% (14/20) of primary and 70% (21/30) of metastatic breast cancer patients; none were captured from patients with non-epithelial cancer (n = 20) or healthy subjects (n = 25). Microfluidic-based single cell transcriptional profiling of 87 cancer-associated and reference genes showed heterogeneity among individual CTCs, separating them into two major subgroups, based on 31 highly expressed genes. In contrast, single cells from seven breast cancer cell lines were tightly clustered together by sample ID and ER status. CTC profiles were distinct from those of cancer cell lines, questioning the suitability of such lines for drug discovery efforts for late stage cancer therapy.Conclusions/significanceFor the first time, we directly measured high dimensional gene expression in individual CTCs without the common practice of pooling such cells. Elevated transcript levels of genes associated with metastasis NPTN, S100A4, S100A9, and with epithelial mesenchymal transition: VIM, TGFß1, ZEB2, FOXC1, CXCR4, were striking compared to cell lines. Our findings demonstrate that profiling CTCs on a cell-by-cell basis is possible and may facilitate the application of 'liquid biopsies' to better model drug discovery.

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Transcriptional profiling of human breast cancer cell lines

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