Estrogen receptor action in three dimensions - looping the loop.

Due to advances in genomic technologies, our understanding of estrogen receptor (ER)-mediated transcription in breast cancer cells has evolved significantly in recent years. Genome-wide mapping experiments revealed thousands of ER-binding events, but linking them to the target genes has been an ongoing struggle. A recent paper describes a new technique, called ChIA-PET (chromatin interaction analysis using paired-end tag sequencing), that can directly address these questions. ChIA-PET is an unbiased approach for simultaneously identifying all genome-wide binding events of a transcription factor and those involved in long-range chromatin loops

FoxA1 is a key mediator of hormonal response in breast and prostate cancer.

Hormonally regulated breast and prostate cancers are the most common cause of cancer in females and males respectively. FoxA1 acts as a pioneer factor for both androgen receptor (AR) and estrogen receptor-α (ER), dictating the binding location, and therefore function of these transcription factors. It is an essential protein for the transcriptional activity of both ER and AR, yet it has distinct roles with the two different nuclear receptors. In both malignancies, FoxA1 plays a pivotal role from early stage cancer through to drug resistant and metastatic disease. Due to this key role in mediating ER and AR function, FoxA1 is not only an attractive therapeutic target but could potentially function as a novel biomarker

Comprehensive Genomic Analysis Reveals that the Pioneering Function of FOXA1 Is Independent of Hormonal Signaling.

Considerable work has linked hormone receptors, such as estrogen receptor-alpha (ER), with the pioneer factor FOXA1. Altered FOXA1 levels contribute to endocrine-resistant breast cancer, where it maintains ER-chromatin interactions, even in contexts in which cells are refractory to ER-targeted drugs. A recent study controversially suggests that FOXA1 binding can be induced by hormonal pathways, including the estrogen-ER complex. We now show that the vast majority (>99%) of FOXA1 binding events are unaffected by steroid activation. A small number (<1%) of FOXA1 binding sites appear to be induced by estrogen, but these are created from chromatin interactions between ER binding sites and adjacent FOXA1 binding sites and do not represent genuine new FOXA1-pioneering elements. FOXA1 is therefore not regulated by estrogen and remains a bone fide pioneer factor that is entirely upstream of the ER complex.ERC Consolidator award (Project number 646876), CRUK funding and a Komen Scholarship

A co-ordinated interaction between CTCF and ER in breast cancer cells.

BACKGROUND: CCCTC-binding factor (CTCF) is a conserved zinc finger transcription factor that is involved in both intra- and interchromasomal looping. Recent research has shown a role for CTCF in estrogen receptor (ER) biology, at some individual loci, but a multi-context global analysis of CTCF binding and transcription activity is lacking. RESULTS: We now map CTCF binding genome wide in breast cancer cells and find that CTCF binding is unchanged in response to estrogen or tamoxifen treatment. We find a small but reproducible set of CTCF binding events that overlap with both the nuclear receptor, estrogen receptor, and the forkhead protein FOXA1. These overlapping binding events are likely functional as they are biased towards estrogen-regulated genes, compared to regions lacking either CTCF or ER binding. In addition we identify cell-line specific CTCF binding events. These binding events are more likely to be associated with cell-line specific ER binding events and are also more likely to be adjacent to genes that are expressed in that particular cell line. CONCLUSION: The evolving role for CTCF in ER biology is complex, but is likely to be multifunctional and possibly influenced by the specific genomic locus. Our data suggest a positive, pro-transcriptional role for CTCF in ER-mediated gene expression in breast cancer cells. CTCF not only provides boundaries for accessible and 'protected' transcriptional blocks, but may also influence the actual binding of ER to the chromatin, thereby modulating the estrogen-mediated gene expression changes observed in breast cancer cells.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

FOXA1 mutations in hormone-dependent cancers.

The forkhead protein, FOXA1, is a critical interacting partner of the nuclear hormone receptors, oestrogen receptor-α (ER) and androgen receptor (AR), which are major drivers of the two most common cancers, namely breast and prostate cancer. Over the past few years, progress has been made in our understanding of how FOXA1 influences nuclear receptor function, with both common and distinct roles in the regulation of ER or AR. Recently, another level of regulation has been described, with the discovery that FOXA1 is mutated in 1.8% of breast and 3-5% prostate cancers. In addition, a subset of both cancer types exhibit amplification of the genomic region encompassing the FOXA1 gene. Furthermore, there is evidence of somatic changes that influence the DNA sequence under FOXA1 binding regions, which may indirectly influence FOXA1-mediated regulation of ER and AR activity. These recent observations provide insight into the heterogeneity observed in ER and AR driven cancers

Defining and targeting transcription factors in cancer.

A report from the Keystone Symposium on Molecular and Cellular Biology, 'Deregulation of transcription in cancer: controlling cell fate decisions', Killarney, Ireland, 21-26 July 2009

Signaling pathways and steroid receptors modulating estrogen receptor α function in breast cancer.

Estrogen receptor α (ER) is the major driver of ∼75% of breast cancers, and multiple ER targeting drugs are routinely used clinically to treat patients with ER+ breast cancer. However, many patients relapse on these targeted therapies and ultimately develop metastatic and incurable disease, and understanding the mechanisms leading to drug resistance is consequently of utmost importance. It is now clear that, in addition to estrogens, ER function is modulated by other steroid receptors and multiple signaling pathways (e.g., growth factor and cytokine signaling), and many of these pathways affect drug resistance and patient outcome. Here, we review the mechanisms through which these pathways impact ER function and drug resistance as well as discuss the clinical implications.R.S. is funded by the Novo Nordisk Foundation (NNF15OC0014136). S.K. is funded by Cancer Research UK. J.S.C. is funded by Cancer Research UK, an ERC Consolidator Award, and a Komen Scholarship

RIME proteomics of estrogen and progesterone receptors in breast cancer.

Nuclear receptors play an important role in transcriptional regulation of diverse cellular processes and is also relevant in diseases such as cancer. In breast cancer, the nuclear receptors - estrogen receptor (ER) and progesterone receptor (PR) are classical markers of the disease and are used to classify breast cancer subtypes. Using a recently developed affinity purification MS technique (RIME) [1], we investigate the protein interactors of ER and PR in breast cancer cell lines upon stimulation by the ligands - estrogen and progesterone. The data is deposited at proteomeXchange (PXD002104) and is part of a publication [2] that explains the link between the two nuclear receptors and potential consequences of this in breast cancer. In this manuscript, we describe the methodology used and provide details on experimental procedures, analysis methods and analysis of raw data. The purpose of this article is to enable reproducibility of the data and provide technical recommendations on performing RIME in hormonal contexts