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ChIP-Seq Study Uncovers Outcome-Related Estrogen Receptor Binding Patterns in Breast Cancers

NEW YORK (GenomeWeb News) – In a study appearing online today in Nature, researchers from the UK and the Czech Republic reported that they have been able to discern distinct estrogen receptor-binding sites — and related gene expression profiles — in ER-positive breast cancer genomes from individuals with poor or more positive clinical outcomes.

The group used chromatin immunoprecipitation sequencing to map ER-binding patterns across the genomes of primary breast cancer and metastasis samples, looking at how the binding sites differed depending on the type of tumor, clinical outcomes, and drug susceptibility. The work uncovered a shared set of ER-binding sites in breast cancers characterized by enhanced estrogen receptor alpha expression. But it also revealed shifts in ER-binding sites in ER-positive tumors that coincided with differential gene expression and patient prognoses.

"[W]e show that there is plasticity in ER-binding capacity, with distinct combinations of cis-regulatory elements linked with the different clinical outcomes," University of Cambridge researchers Jason Carroll and Carlos Caldas, the study's corresponding authors, and their colleagues wrote.

"By mapping ER binding in clinical samples, we provide a first glimpse of the primary regulatory regions that contribute to differences within [ER-positive] breast cancer, rather than secondary events such as gene expression profiles," they added.

Estrogen receptor expression status is one of several features used to classify breast cancers. But since the receptor acts as a transcription factor, the study authors explained, knowing when and where it binds in breast cancer genomes is also expected to offer insights into the genes that it regulates and to related tumor traits.

Whereas past studies of ER-binding sites in breast cancer genomes have mainly focused on cell lines, the team decided to look at where the receptor was bound in primary and metastatic tumor samples from breast cancer patients.

"We sought to interrogate ER-binding events, for the first time, in primary frozen breast cancer samples, to determine if ER binding is dynamic and if specific cis-regulatory elements can distinguish tumors from patients with distinct clinical outcomes," they wrote.

To do this, researchers did ChIP-Seq on seven ER-positive primary tumors from individuals with poor outcomes and eight ER-positive tumors from patients with better outcomes using the Illumina Genome Analyzer and antibodies directed against the estrogen receptor. They also used a similar strategy to assess ER-binding in two ER-negative breast cancer controls and in three ER-positive metastasis samples.

Along with a set of nearly 500 ER-binding sites that were found in most of the ER-positive tumors, the researchers used differential binding analyses to track down 1,192 sites with more pronounced ER-binding in the poor prognosis group. Another 599 sites showed enhanced ER-binding in tumors from individuals with more favorable outcomes.

By looking at the genes neighboring these variable ER-binding sites, the team was able to come up with gene expression signatures for predicting metastasis-free survival in an independent set of ER-positive tumor samples.

Using a similar ChIP-Seq approach, they also explored ER-binding patterns in drug-sensitive or -resistant breast cancer cell lines.

Although resistance to the drug tamoxifen corresponded to enhanced ER-binding at many of the same sites seen in tumors from individuals with poor clinical outcomes, though, that comparison suggested that even wild type MCF-7 breast cancer cells shared many ER-binding sites with tumors from those with poor outcomes or metastases.

From their subsequent experiments in cell lines, the researchers saw that some of the same signals that spur metastasis or drug resistance in breast cancer also lead to rearrangements in ER-binding profiles, including enhanced binding of the receptor at thousands of spots in the genome.

In addition, from experiments on ER-positive breast cancers that had metastasized to the brain, liver, or bone, researchers concluded that FOXA1 — a pioneer factor frequently co-expressed with the receptor in metastases — influences such metastasis-related shifts in ER-binding patterns.

"A remaining question is what dictates differential FOXA1 and subsequently ER binding," they wrote. "Possibilities include changes in the genomic landscape, alterations in co-factor levels or changes in FOXA1 structure and function, potentially by post-translational modifications."

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