Use of global gene expression patterns in mechanistic studies of oestrogen action in MCF7 human breast cancer cells

• Published in: Journal of steroid biochemistry and molecular biology Vol. 114; no. 1; pp. 21 - 32
• Main Authors: Sadler, A.J., Pugazhendhi, D., Darbre, P.D.
• Format: Journal Article Conference Proceeding
• Language: English
• Published: Kidlington Elsevier Ltd 01-03-2009; Elsevier
• Subjects: Animals; Antioestrogen; Antioestrogen resistance; Biological and medical sciences; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Cell Line, Tumor - drug effects; Cell Line, Tumor - metabolism; Environmental oestrogens; Estradiol - analogs & derivatives; Estradiol - pharmacology; Estrogen Antagonists - pharmacology; Estrogens - metabolism; Female; Fulvestrant; Fundamental and applied biological sciences. Psychology; Gene Expression Profiling; Gene Expression Regulation, Neoplastic - drug effects; Global gene expression; Humans; Long-term oestrogen deprivation; Microarray; Molecular Sequence Data; Oestrogen; Oligonucleotide Array Sequence Analysis; Parabens; Vertebrates: endocrinology; Vertebrates: reproduction; Environmental oestrogens; Oestrogen; Antioestrogen resistance; Breast cancer; Global gene expression; Microarray; Long-term oestrogen deprivation; Antioestrogen; Fulvestrant; Parabens; Human; Estrogen; Gene expression; Long term; Ovarian hormone; Sex steroid hormone
• ISSN: 0960-0760; 1879-1220
• DOI: 10.1016/j.jsbmb.2008.12.017

Over the years, the MCF7 human breast cancer cell line has provided a model system for the study of cellular and molecular mechanisms in oestrogen regulation of cell proliferation and in progression to oestrogen and antioestrogen independent growth. Global gene expression profiling has shown that oestrogen action in MCF7 cells involves the coordinated regulation of hundreds of genes across a wide range of functional groupings and that more genes are downregulated than upregulated. Adaptation to long-term oestrogen deprivation, which results in loss of oestrogen-responsive growth, involves alterations to gene patterns not only at early time points (0–4 weeks) but continuing through to later times (20–55 weeks), and even involves alterations to patterns of oestrogen-regulated gene expression. Only 48% of the genes which were regulated ≥2-fold by oestradiol in oestrogen-responsive cells retained this responsiveness after long-term oestrogen deprivation but other genes developed
de novo oestrogen regulation. Long-term exposure to fulvestrant, which resulted in loss of growth inhibition by the antioestrogen, resulted in some very large fold changes in gene expression up to 10,000-fold. Comparison of gene profiles produced by environmental chemicals with oestrogenic properties showed that each ligand gave its own unique expression profile which suggests that environmental oestrogens entering the human breast may give rise to a more complex web of interference in cell function than simply mimicking oestrogen action at inappropriate times.