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Search Results: 1 - 10 of 84 matches for " Steffi Oesterreich "
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Estrogen-repressed genes – key mediators of estrogen action?
Simeen Zubairy, Steffi Oesterreich
Breast Cancer Research , 2005, DOI: 10.1186/bcr1271
Abstract: There are a handful of studies that report estrogen-mediated repression of genes, with some of them also addressing potential mechanisms. For example, the ErbB2 proto-oncogene is repressed by estrogen [2]. This repression seems to result from competition between estrogen-bound ER-α and another transcription factor (most likely activator protein [AP]-2) for the coactivator steroid receptor coactivator (SRC)-1, because overexpression of SRC-1, but not SRC-2 or SRC-3, relieves repression of ErbB2. This gives rise to the question of whether estrogen-mediated repression really involves 'classical' repression, or merely represents a loss of basal transcription caused by squelching (i.e. competition for a limited pool of coactivators) or simple displacement of coactivators.There is some evidence that corepressors can play a role in estrogen-mediated repression of genes. Overexpression of the corepressors SMRT (silencing mediator for retinoid and thyroid hormone receptors) and SAFB1 (scaffold attachment factor B1) enhanced repression of folate receptor-α [3] and E-cadherin [4], respectively. In contrast, none of the ER-α coactivators tested (including SRC family members) affected the repression of folate receptor-α by estrogen [3]. Interestingly, depletion of the corepressor DP97 attenuated the repression of ErbB2 [5]. These data suggest that corepressors are involved in repression, but is this really an active recruitment of corepressors to the promoters of target genes? Clearly, interaction of corepressors with ER-α in the presence of estrogen does not fit the classical model in which estrogen-bound ER-α interacts with coactivators, whereas antiestrogen-bound ER-α preferentially interacts with corepressors. However, based on a few studies showing that some corepressors can bind ER-α in the presence of estrogen and that coactivators and corepressors coexist in complexes, it might be timely to revisit this model.Another open question is whether nonclassical ER-α pathways ar
26th Annual San Antonio Breast Cancer Symposium, San Antonio, Texas, USA, 3–6 December 2003: update on preclinical and translational research
Adrian V Lee, Gary Chamness, Steffi Oesterreich
Breast Cancer Research , 2004, DOI: 10.1186/bcr758
Abstract: The 26th Annual San Antonio Breast Cancer Symposium was held in San Antonio, Texas on 3–6 December 2003. Over the past 26 years this meeting has evolved into the largest conference in the world devoted solely to breast cancer research. This year there were more than 700 abstract presentations, from 6000 attendees representing 80 countries. This not only included physicians and scientists who presented the newest information on prevention, diagnosis, and treatment of breast cancer, but also included breast cancer patient advocates. In the spirit of the late William L McGuire, who co-founded this symposium with Charles A Coltman Jr in 1978, cellular and molecular biology with translational potential was presented, and the highlights will now be discussed.The meeting was opened by a plenary lecture on stem cells in normal breast development and breast cancer by Max Wicha (University of Michigan, Ann Arbor, Michigan, USA). Wicha pointed out that many features of stem cells are also shared with breast cancer cells, including the ability to self renew and differentiate, telomerase activity, resistance to damaging agents, and anchorage-independent growth and survival (abstract P1 [1]).Wicha has developed a new in vitro culture system allowing the propagation of putative stem cells from normal breast tissue [2]. In this situation, cells grow in perfect spheroids, termed mammospheres, and show the two classic features of stem cells: the ability both to self renew and to differentiate. Microarray analysis of these cells showed expression of many genes that are similar to those expressed in hemopoetic cells, neuronal cells, and embryonic stem cells. Importantly, when overexpressed in the mammary gland, many of these genes result in tumorigenesis.Wicha went on to show that breast cancers contain putative cancer stem cells that can be selected by specific cell surface markers such as CD44 and CD24. Blockade of the Notch 4 ligand, which is highly expressed in normal stem cells, c
Whole Genome Amplification of DNA for Genotyping Pharmacogenetics Candidate Genes
Santosh Philips,Steffi Oesterreich,Todd C. Skaar
Frontiers in Pharmacology , 2012, DOI: 10.3389/fphar.2012.00054
Abstract: Whole genome amplification (WGA) technologies can be used to amplify genomic DNA when only small amounts of DNA are available. The Multiple Displacement Amplification Phi polymerase based amplification has been shown to accurately amplify DNA for a variety of genotyping assays; however, it has not been tested for genotyping many of the clinically relevant genes important for pharmacogenetic studies, such as the cytochrome P450 genes, that are typically difficult to genotype due to multiple pseudogenes, copy number variations, and high similarity to other related genes. We evaluated whole genome amplified samples for Taqman? genotyping of SNPs in a variety of pharmacogenetic genes. In 24 DNA samples from the Coriell human diversity panel, the call rates, and concordance between amplified (~200-fold amplification) and unamplified samples was 100% for two SNPs in CYP2D6 and one in ESR1. In samples from a breast cancer clinical trial (Trial 1), we compared the genotyping results in samples before and after WGA for three SNPs in CYP2D6, one SNP in CYP2C19, one SNP in CYP19A1, two SNPs in ESR1, and two SNPs in ESR2. The concordance rates were all >97%. Finally, we compared the allele frequencies of 143 SNPs determined in Trial 1 (whole genome amplified DNA) to the allele frequencies determined in unamplified DNA samples from a separate trial (Trial 2) that enrolled a similar population. The call rates and allele frequencies between the two trials were 98 and 99.7%, respectively. We conclude that the whole genome amplified DNA is suitable for Taqman? genotyping for a wide variety of pharmacogenetically relevant SNPs.
To bind or not to bind - FoxA1 determines estrogen receptor action in breast cancer progression
Rebecca J Watters, Panayiotis V Benos, Steffi Oesterreich
Breast Cancer Research , 2012, DOI: 10.1186/bcr3146
Abstract: Patients with breast cancer that express estrogen receptor-alpha (ERα+) are candidates for endocrine therapies. Although endocrine therapies are among the most successful targeted therapies in oncology, a significant subset of ER+ breast cancers have become resistant to them. The activation of growth factor receptor (GFR) pathways has been identified as a possible culprit, and although ER is rarely mutated in endocrine-resistant tumors, it can be aberrantly activated by GFR signaling in a ligand-independent manner [1].Over the last few years, the application of chromatin immunoprecipitation (ChIP) coupled with massively parallel sequencing (ChIP-seq) enabled the identification of the ER cistrome in breast cancer cells [2]. By showing the following, the results brought an end to the dogma that ER binds primarily to the proximal promoters: (a) ER frequently binds distal enhancers [3], (b) the forkhead protein FoxA1 is necessary for ER-chromatin interactions [3-6], and (c) activation of GFR signaling results in the redirection of ER binding [7]. However, all previous studies, though highly informative, were performed in cell lines (primarily MCF-7 cells). Obtaining ChIP-seq results from primary breast tumors was the next step that everyone was eagerly awaiting.Ross-Innes and colleagues [8] analyzed ER ChIP-seq data from 15 ER+ tumors (eight with a good prognosis and seven with a poor prognosis) and three distant metastases. The authors found a core set of 484 ER-binding events present in at least 75% of all ER+ tumors (but not in the ER? controls). Intriguingly, ER-binding signal intensity was highest in metastatic samples and lowest in patients with good outcomes, suggesting that binding intensity may correspond to disease progression. Differential binding analysis found 1,192 ER-binding events that were stronger in the poor prognosis/metastasis group in comparison with the good outcome samples and found 599 binding events more prevalent in the good outcome tumors. Mo
Epigenetics in breast cancer: what's new?
Yi Huang, Shweta Nayak, Rachel Jankowitz, Nancy E Davidson, Steffi Oesterreich
Breast Cancer Research , 2011, DOI: 10.1186/bcr2925
Abstract: While the term epigenetics is often used loosely, and sometimes in rather different ways, the term is generally considered to encompass changes in DNA methylation, histone modifications, miRNA expression, and nucleo-some positioning and higher order chromatin as epigenetic changes affecting gene regulation. Epigenetics was defined as a discipline more than 50 years ago, by CH Waddington, and originally described changes in the development of organisms that could not be explained by changes in DNA. Subsequently it became clear that epigenetic modifications play important roles in diseases, including breast cancer. There is thus a pressing need to understand the functional genome; that is, the changes defined by regulatory mechanisms overlaying the genetic structure.Over the past few years there has been an explosion in studies of epigenetics in breast cancer, reflected by the exponential increase of published manuscripts (Figure 1). A PubMed search for the keywords 'epigenetic' and 'breast cancer' reveals that the first publication was in 1983. Progress was slow until approximately 10 years ago when the number of studies started to steadily increase, at least in part fueled by improved technologies. In the present review, we focus on recent advances in the understanding of histone methylation and demethylation, a relatively new area with promise for clinical translation. We also review recent studies that have utilized genome-wide technologies for the study of DNA methylation. Much progress has been made in the characterization of noncoding RNAs, and the effect of higher order chromatin structure on gene expression in breast cancer; however, these discoveries lie outside the scope of our review.Finally, we also discuss the relatively slow translation of results from the epigenetic field into the clinic. Although there has been a dramatic increase of research into the epigenetics of breast cancer and milestone discoveries have undoubtedly been made, the application of
The role of single nucleotide polymorphisms in breast cancer metastasis
James M Rae, Todd C Skaar, Susan G Hilsenbeck, Steffi Oesterreich
Breast Cancer Research , 2008, DOI: 10.1186/bcr1842
Abstract: Modern genetics has been applied to many aspects of breast cancer. For example, it is well established that inherited mutations in BCRA1 and BCRA2 can predispose women to this disease, as well as to ovarian cancer [1]. Changes in other genes, such as p53, PTEN, or CHEK2, are also associated with increased risk of breast cancer. Recent genome-wide association studies have led to the identification of numerous polymorphisms associated with increased risk for breast cancer, with FGFR2 being one of the top candidate genes [2,3]. Also, numerous ongoing studies are being carried out to understand whether there is a heritable genetic contribution to therapeutic responses in breast cancer patients [4]. Because of the importance of metastasis in the prognosis of breast cancer patients, it is important to determine whether germ line polymorphisms also play a role in breast cancer metastasis. Indeed, there is a paucity of data from microarray and other studies to fully explain breast cancer metastasis from tumor somatic cell evolution, thus opening the question of whether germline polymorphisms could contribute to breast cancer metastasis.Recent studies in mice indicate that inherited genetic backgrounds can influence metastatic potential. The elucidation of the causal genetic variants in these models may lead to the identification of important metastasis genes and heritable genetic variants that predispose humans to breast cancer metastasis. Using the MMTV-PyMT transgenic mouse model, which develops mammary tumors with 100% penetrance, Hunter and colleagues [5] have shown that the incidence of pulmonary metastasis was influenced by the mouse genetic background. They found that the AKR and FVB stains show high metastatic efficiency, while two others (DBA and NZB) show low rates of metastasis. Quantitative trait genetic mapping analysis identified a probable metastasis efficiency locus (Mtes1) on mouse chromosome 19 in a 10 Mb region orthologous to human chromosome 11q12-13. Al
Development and Evaluation of the Posttraumatic Growth Status Inventory  [PDF]
Tatjana Alexander, Rainer Oesterreich
Psychology (PSYCH) , 2013, DOI: 10.4236/psych.2013.411120

Posttraumatic growth reflects beneficial psychological processes in persons with traumatic experiences. Existing measures of growth were criticized due to their retrospective self-report format that may cause biases in capturing the growth processes in individuals with several specific kinds of trauma, such as physical or psychological disabilities of close family members, bereavement and some others kinds of traumatic experience. In this case, the feelings of guilt may prevent the persons from being aware of the favorable personal changes. The objective of this study was to develop and to evaluate an alternative measuring instrument that uses a status quo response format instead of retrospective items and covers additional areas of growth-related changes. The samples comprised 440 adult persons with traumatic experience, including 181 parents of children with mental and/or physical disabilities. Exploratory and confirmatory factor analyses revealed a 7-factors solution, corresponding to the following subscales: Relationships to Others, New Possibilities, Personal Strength, Appreciation of Life, Spiritual Changes, Generativity, and Openness. Results showed good reliability and concurrent validity. The PGSI is recommended particularly for use in longitudinal studies as well as in samples of persons whose trauma relates to a severe psychological or physical disability in their families.

Scaffold attachment factor B1 (SAFB1) heterozygosity does not influence Wnt-1 or DMBA-induced tumorigenesis
Benny Kaipparettu, Klaudia M Dobrzycka, Ora Britton, Adrian V Lee, Alan J Herron, Yi Li, Michael T Lewis, Daniel Medina, Steffi Oesterreich
Molecular Cancer , 2009, DOI: 10.1186/1476-4598-8-15
Abstract: We crossed female SAFB1+/- (C57B6/129) mice with male MMTV-Wnt-1 (C57B6/SJL) mice to obtain SAFB1+/+/Wnt-1, SAFB1+/-/Wnt-1, and SAFB1+/- mice. For the chemical induced tumorigenesis study we treated 8 weeks old SAFB1+/- and SAFB+/+ BALB/c mice with 1 mg DMBA once per week for 6 weeks. Animals were monitored for tumor incidence and tumor growth. Tumors were characterized by performing H&E, and by staining for markers of proliferation and apoptosis.We did not detect significant differences in tumor incidence and growth between SAFB1+/+/Wnt-1 and SAFB1+/-/Wnt-1 mice, and between DMBA-treated SAFB1+/+ and SAFB1+/-mice. Histological evaluation of tumors showed that SAFB1 heterozygosity did not lead to changes in proliferation or apoptosis. There were, however, significant differences in the distribution of tumor histologies with an increase in papillary and cribriform tumors, and a decrease in squamous tumors in the SAFB1+/-/Wnt-1 compared to the SAFB1+/+/Wnt-1 tumors. Of note, DMBA treatment resulted in shortened survival of SAFB1+/- mice compared to their wildtype littermates, however this trend did not reach statistical significance.Our data show that SAFB1 heterozygosity does not influence Wnt-1 or DMBA-induced mammary tumorigenesis.Scaffold Attachment Factor B1 (SAFB1) is a multifunctional protein that is involved in RNA processing, transcriptional regulation, and stress response [1]. SAFB1 has previously been implicated in breast tumorigenesis. SAFB1 functions as an estrogen receptor α (ERα) corepressor [2], and its overexpression in cultured cells leads to growth inhibition. Importantly, SAFB1 mutations have been identified in microdissected breast tumors but not in the normal adjacent tissue, and SAFB1's chromosomal locus displays extremely high loss of heterozygocity LOH (78%) in invasive breast cancer [3]. There is no significant different in LOH frequencies between ER-positive and ER-negative tumors, and other in vitro observations [4] suggest that SAFB1 could
Novel Modeling of Combinatorial miRNA Targeting Identifies SNP with Potential Role in Bone Density
Claudia Coronnello ,Ryan Hartmaier,Arshi Arora,Luai Huleihel,Kusum V. Pandit,Abha S. Bais,Michael Butterworth,Naftali Kaminski,Gary D. Stormo,Steffi Oesterreich,Panayiotis V. Benos
PLOS Computational Biology , 2012, DOI: 10.1371/journal.pcbi.1002830
Abstract: MicroRNAs (miRNAs) are post-transcriptional regulators that bind to their target mRNAs through base complementarity. Predicting miRNA targets is a challenging task and various studies showed that existing algorithms suffer from high number of false predictions and low to moderate overlap in their predictions. Until recently, very few algorithms considered the dynamic nature of the interactions, including the effect of less specific interactions, the miRNA expression level, and the effect of combinatorial miRNA binding. Addressing these issues can result in a more accurate miRNA:mRNA modeling with many applications, including efficient miRNA-related SNP evaluation. We present a novel thermodynamic model based on the Fermi-Dirac equation that incorporates miRNA expression in the prediction of target occupancy and we show that it improves the performance of two popular single miRNA target finders. Modeling combinatorial miRNA targeting is a natural extension of this model. Two other algorithms show improved prediction efficiency when combinatorial binding models were considered. ComiR (Combinatorial miRNA targeting), a novel algorithm we developed, incorporates the improved predictions of the four target finders into a single probabilistic score using ensemble learning. Combining target scores of multiple miRNAs using ComiR improves predictions over the na?ve method for target combination. ComiR scoring scheme can be used for identification of SNPs affecting miRNA binding. As proof of principle, ComiR identified rs17737058 as disruptive to the miR-488-5p:NCOA1 interaction, which we confirmed in vitro. We also found rs17737058 to be significantly associated with decreased bone mineral density (BMD) in two independent cohorts indicating that the miR-488-5p/NCOA1 regulatory axis is likely critical in maintaining BMD in women. With increasing availability of comprehensive high-throughput datasets from patients ComiR is expected to become an essential tool for miRNA-related studies.
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Roettgen, Steffi
Zeitenblicke , 2003,
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