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WIREs Syst Biol Med
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Estrogen receptor‐positive breast cancer: a multidisciplinary challenge

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Abstract Estrogen receptor (ER)‐positive breast cancer research is an ideal example of how systems biology can be applied to better understand a specific clinical issue. By integrating vast data sets from tumor‐derived expression arrays, genome‐wide transcription factor/chromatin interactions, proteomics and computational analyses, we may better understand the concept of breast cancer development, heterogeneity, and its treatment. Resistance to endocrine treatment, such as anti‐estrogens, often occurs and systems biology may prove to be a valuable asset in tailoring treatment for each patient. In such a multidisciplinary setup, it is essential to try and connect these massive data streams with the known pathological background and cell biology. In this review, we describe the current status of such studies and the challenges that are to be met in order to fully understand the concept of anti‐estrogen resistance from a holistic perspective. WIREs Syst Biol Med 2011 3 216–230 DOI: 10.1002/wsbm.109 This article is categorized under: Models of Systems Properties and Processes > Cellular Models Laboratory Methods and Technologies > Genetic/Genomic Methods Translational, Genomic, and Systems Medicine > Translational Medicine

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Applying biophysics in studying estrogen receptor functioning. Biophysical techniques, including fluorescence recovery after photobleaching (FRAP) and fluorescence resonance energy transfer (FRET), allow us to study the dynamics of protein‐chromatin interactions, protein–protein interactions, and protein conformation in living cells in real time. In FRAP, the fluorescence of the tagged protein is bleached by a high‐intensity laser, after which the recovery of the fluorescent signal (and thereby the migration speed of the tagged protein) is monitored. In FRET, the energy transfer of a donor fluorophore (in this case CFP) towards an acceptor fluorophore (in this case YFP) is monitored. FRET is highly dependent on distance and orientation between the two fluorophores, allowing the detection of protein–protein interactions and protein conformational changes in intact living cells.

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Systems biology in breast cancer treatment and drug selection. A scheme by which systems biology may be applied in tailoring endocrine treatment through individualized drug selection. From tumor material of each patient, immunohistochemistry, expression arrays, ChIP‐seq, and sequencing for genetic alterations are performed in order to gain insights in the tumor's unique genomic and cellular features. Through computational analyses and data mining, key players in the cellular pathways that underlie tumorogenesis and progression are identified. Then, specific drugs are selected that inhibit these key players, either alone or in conjunction with other agents, and administered to the patient. This way, individually optimized breast cancer treatment could be achieved for each patient through the use of multidisciplinary systems biology.

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Combining photobleaching and chromatin immunoprecipitation (ChIP): two different frequencies. A model is proposed, in which we try to reconcile the differences in timescale that are detected when studying estrogen receptor (ER)–chromatin interactions using fluorescence recovery after photobleaching (FRAP; seconds) or ChIP (min). In vehicle, ER 'scans' the chromatin with highly transient interactions, that can be detected by FRAP but not by ChIP. When the cell is stimulated with E2, ER exposes two different frequencies of interaction; a high frequency in the order of seconds (detected by FRAP) and a low frequency in the order of minutes (detected by ChIP).

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From cells to DNA, a schematic overview of advances in genomics. The technological boost of the last decade has led to the identification of the genome‐wide binding repertoire of transcription factors and chromatin modifications, starting from cells into culture and ending with a genome browser for visualization. Here, we depict the CTSD locus, a bona‐fine transcription target of estrogen receptor in breast cancer cells, showing how ERα, FoxA1, and GATA3 all bind at the same site 30 kb upstream of the CTSD promoter, which results in a massive accumulation of Pol‐II throughout the gene.

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Translational, Genomic, and Systems Medicine > Translational Medicine
Laboratory Methods and Technologies > Genetic/Genomic Methods
Models of Systems Properties and Processes > Cellular Models

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