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The gene expression response of breast cancer to growth regulators: patterns and correlation with tumor expression
Heather E Cunliffe1, Markus Ringnér, Sven Bilke
1Cancer Genetics Branch, National Human Genome Research Institute/NIH, 50 South Drive, Bethesda, MD 20892, USA.
Abstract:
The effects of hormone and growth factor signaling on gene expression contribute significantly to breast tumorigenesis and disease progression; however, the targets of signaling networks associated with deregulated growth are not well understood. We defined the dynamic transcriptional effects elicited in MCF7, T-47D, and MDA-MB-436 breast cancer cell lines by nine regulators of growth and differentiation (17beta-estradiol, antiestrogens fulvestrant and tamoxifen, progestin R5020, antiprogestin RU486, all-trans-retinoic acid, epidermal growth factor, mitogen-activated protein/extracellular signal-regulated kinase 1/2 inhibitor U0126 and phorbol ester 12-O-tetradecanoylphorbol-13-acetate) and compared the patterns of gene regulation to published tumor expression profiles. The complex pattern of response to these agents revealed unexpected relationships between their effects, including a profound overlap in genes regulated by both steroids and epidermal growth factor, and striking overlaps between fulvestrant and all-trans-retinoic acid. Estrogen-responsive genes could be divided into two major clusters, only one of which is associated with cell proliferation. Gene ontology analysis was used to highlight functionally distinct biological responses to different mitogens. Significant correlations were identified between several clusters of drug-responsive genes and genes that discriminate estrogen receptor status or disease outcome in patient samples. The majority of estrogen receptor status discriminators were not responsive in our dataset and are therefore likely to reflect underlying differences in histogenesis and disease progression rather than growth factor signaling. This article highlights the overall impact at the gene expression level of diverse regulators of breast cancer growth and links the behavior of breast cancer cells in culture to important clinical properties of human breast tumors.
Insights
This study reveals how hormones and growth factors impact gene expression in breast cancer cells, uncovering links between cellular responses and patient tumor characteristics. Understanding these gene regulation patterns is key to breast cancer progression.
Area of Science:
- Molecular biology
- Genomics
- Cancer research
Background:
- Hormone and growth factor signaling are crucial in breast cancer development and progression.
- The specific gene targets of signaling networks driving deregulated breast cancer growth remain largely unknown.
Purpose of the Study:
- To investigate the dynamic transcriptional effects of various growth regulators on breast cancer cell lines.
- To compare these gene regulation patterns with published tumor expression profiles.
- To identify relationships between signaling pathways and clinical properties of breast tumors.
Main Methods:
- Treatment of three breast cancer cell lines (MCF7, T-47D, MDA-MB-436) with nine different regulators of growth and differentiation.
- Analysis of dynamic transcriptional effects and gene expression patterns.
- Comparison of cell line data with published tumor expression profiles.
- Gene ontology analysis to identify distinct biological responses.
- Correlation analysis between drug-responsive genes and genes associated with estrogen receptor status and disease outcome.
Main Results:
- Identified complex gene regulation patterns with unexpected overlaps between steroids and epidermal growth factor, and between fulvestrant and all-trans-retinoic acid.
- Divided estrogen-responsive genes into two clusters, with only one linked to cell proliferation.
- Highlighted functionally distinct biological responses to different mitogens using gene ontology.
- Found significant correlations between drug-responsive gene clusters and genes predicting estrogen receptor status or patient outcomes.
- Determined that most estrogen receptor status discriminators likely reflect intrinsic tumor differences rather than growth factor signaling.
Conclusions:
- Diverse regulators of breast cancer growth have a significant impact on gene expression.
- Cellular responses in culture correlate with key clinical properties of human breast tumors.
- The study provides insights into the complex interplay of signaling networks in breast cancer progression and identifies potential therapeutic targets.
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