Nuclear receptor coregulator SNP discovery and impact on breast cancer risk

Hartmaier, Ryan J.; Tchatchou, Sandrine; Richter, Alexandra; Wang, Jay; McGuire, Sean E.; Skaar, Todd C.; Rae, Jimmy M.; Hemminki, Kari; Sutter, Christian; Ditsch, Nina; Bugert, Peter; Weber, Bernhard H. F.; Niederacher, Dieter; Arnold, Norbert; Varon-Mateeva, Raymonda; Wappenschmidt, Barbara; Schmutzler, Rita K.; Meindl, Alfons; Bartram, Claus R.; Burwinkel, Barbara; Oesterreich, Steffi

doi:10.1186/1471-2407-9-438

Cited by 11 publications

(8 citation statements)

References 22 publications

(26 reference statements)

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“…Current studies have shown that the breast cancer risks are associated with commonly occurring single nucleotide polymorphisms (SNPs) [28–32]. The table SNP (131) (dbSNP build 131) in UCSC (http://genome.ucsc.edu/) was used to identify SNPs near the ER binding sites.…”

Section: Resultsmentioning

confidence: 99%

Identification and Functional Annotation of Genome-Wide ER-Regulated Genes in Breast Cancer Based on ChIP-Seq Data

Ding

Wang

Chen

et al. 2012

Computational and Mathematical Methods in Medicine

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Estrogen receptor (ER) is a crucial molecule symbol of breast cancer. Molecular interactions between ER complexes and DNA regulate the expression of genes responsible for cancer cell phenotypes. However, the positions and mechanisms of the ER binding with downstream gene targets are far from being fully understood. ChIP-Seq is an important assay for the genome-wide study of protein-DNA interactions. In this paper, we explored the genome-wide chromatin localization of ER-DNA binding regions by analyzing ChIP-Seq data from MCF-7 breast cancer cell line. By integrating three peak detection algorithms and two datasets, we localized 933 ER binding sites, 92% among which were located far away from promoters, suggesting long-range control by ER. Moreover, 489 genes in the vicinity of ER binding sites were identified as estrogen response elements by comparison with expression data. In addition, 836 single nucleotide polymorphisms (SNPs) in or near 157 ER-regulated genes were found in the vicinity of ER binding sites. Furthermore, we annotated the function of the nearest-neighbor genes of these binding sites using Gene Ontology (GO), KEGG, and GeneGo pathway databases. The results revealed novel ER-regulated genes pathways for further experimental validation. ER was found to affect every developed stage of breast cancer by regulating genes related to the development, progression, and metastasis. This study provides a deeper understanding of the regulatory mechanisms of ER and its associated genes.

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Section: Resultsmentioning

confidence: 99%

Identification and Functional Annotation of Genome-Wide ER-Regulated Genes in Breast Cancer Based on ChIP-Seq Data

Ding

Wang

Chen

et al. 2012

Computational and Mathematical Methods in Medicine

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“…82 A SRC-3 SNP has been identified that predicts response to chemotherapy for lymphoblastic lymphomas and another SRC-3 SNP has been linked to breast cancer risk. 83,84 Our speculation is that coregulator dysfunction will not be restricted solely to rare genetic conditions such as highly penetrant monogenic genetic diseases. By contrast, many coregulators, including all three SRC coregulators, are not essential for viability and even their complete knockout is not lethal.…”

Section: Coregulator ‘Omics’mentioning

confidence: 99%

Nuclear receptor coregulators: modulators of pathology and therapeutic targets

2012

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The nuclear receptor superfamily includes transcription factors that transduce steroid, thyroid and retinoid hormones and other ligands in conjunction with coregulators. To date, over 350 coregulators have been reported in the literature, and advances in proteomic analyses of coregulator protein complexes have revealed that a far greater number of coregulator-interacting proteins also exist. Coregulator dysfunction has been implicated in diverse pathological states, genetic syndromes and cancer. A hallmark of disease related to the disruption of normal coregulator function is the pleiotropic effect on animal physiology, which is frequently manifested as the dysregulation of metabolic and neurological systems. Coregulators have broad physiological and pathological functions that make them promising new drug targets for diseases such as hormone-dependent cancers. Advances in proteomics, genomics and transcriptomics have provided novel insights into the biology of coregulators at a system-wide level and will lead the way to a new understanding of how coregulators can be evaluated in the context of complex and multifaceted genetic factors, hormones, diet, the environment and stress. Ultimately, better knowledge of the associations that exist between coregulator function and human diseases is expected to expand the indications for the use of future coregulator-targeted drugs.

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“…Under both physiological and pathological conditions, SRC-1 was shown to play an important role in the maintenance of bone mineral density by sex hormones and is necessary for protection against osteopenia and osteoporosis 66 . Interestingly, a genetic polymorphic variant of the SRC-1 protein (SNP-1272S) was found to be associated with a decrease in bone mineral density 52 , 67 .…”

Section: Biological Functions Of Src-1mentioning

confidence: 99%

The Function of Steroid Receptor Coactivator-1 in Normal Tissues and Cancer

Walsh¹,

Qin²,

Tien³

et al. 2012

Int. J. Biol. Sci.

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In 1995, the steroid receptor coactivator-1 (SRC-1) was identified as the first authentic steroid receptor coactivator. Since then, the SRC proteins have remained at the epicenter of coregulator biology, molecular endocrinology and endocrine-related cancer. Cumulative works on SRC-1 have shown that it is primarily a nuclear receptor coregulator and functions to construct highly specific enzymatic protein complexes which can execute efficient and successful transcriptional activation of designated target genes. The versatile nature of SRC-1 enables it to respond to steroid dependent and steroid independent stimulation, allowing it to bind across many families of transcription factors to orchestrate and regulate complex physiological reactions. This review highlights the multiple functions of SRC-1 in the development and maintenance of normal tissue functions as well as its major role in mediating hormone receptor responsiveness. Insights from genetically manipulated mouse models and clinical data suggest SRC-1 is significantly overexpressed in many cancers, in particular, cancers of the reproductive tissues. SRC-1 has been associated with cellular proliferation and tumor growth but its major tumorigenic contributions are promotion and execution of breast cancer metastasis and mediation of resistance to endocrine therapies. The ability of SRC-1 to coordinate multiple signaling pathways makes it an important player in tumor cells' escape of targeted therapy.

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Nuclear receptor coregulator SNP discovery and impact on breast cancer risk

Cited by 11 publications

References 22 publications

Identification and Functional Annotation of Genome-Wide ER-Regulated Genes in Breast Cancer Based on ChIP-Seq Data

Identification and Functional Annotation of Genome-Wide ER-Regulated Genes in Breast Cancer Based on ChIP-Seq Data

Nuclear receptor coregulators: modulators of pathology and therapeutic targets

The Function of Steroid Receptor Coactivator-1 in Normal Tissues and Cancer

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