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Articles by A Beyer
Total Records ( 3 ) for A Beyer
  D Ucar , A Beyer , S Parthasarathy and C. T. Workman
 

Chromatin immunoprecipitation (ChIP-chip) experiments enable capturing physical interactions between regulatory proteins and DNA in vivo. However, measurement of chromatin binding alone is not sufficient to detect regulatory interactions. A detected binding event may not be biologically relevant, or a known regulatory interaction might not be observed under the growth conditions tested so far. To correctly identify physical interactions between transcription factors (TFs) and genes and to determine their regulatory implications under various experimental conditions, we integrated ChIP-chip data with motif binding sites, nucleosome occupancy and mRNA expression datasets within a probabilistic framework. This framework was specifically tailored for the identification of functional and non-functional DNA binding events. Using this, we estimate that only 50% of condition-specific protein–DNA binding in budding yeast is functional. We further investigated the molecular factors determining the functionality of protein–DNA interactions under diverse growth conditions. Our analysis suggests that the functionality of binding is highly condition-specific and highly dependent on the presence of specific cofactors. Hence, the joint analysis of both, functional and non-functional DNA binding, may lend important new insights into transcriptional regulation.

Contact: workman@cbs.dtu.dk

  I Barone , Y Cui , M. H Herynk , A Corona Rodriguez , C Giordano , J Selever , A Beyer , S Ando and S. A.W. Fuqua
 

Aromatase inhibitors (AI) are rapidly becoming the first choice for hormonal treatment of estrogen receptor- (ER)–positive breast cancer in postmenopausal women. However, de novo and acquired resistance frequently occurs. We have previously identified a lysine to arginine transition at residue 303 (K303R) in ER in premalignant breast lesions and invasive breast cancers, which confers estrogen hypersensitivity and resistance to tamoxifen treatment. Thus, we questioned whether resistance to AIs could arise in breast cancer cells expressing the ER mutation. As preclinical models to directly test this possibility, we generated K303R-overexpressing MCF-7 cells stably transfected with an aromatase expression vector. Cells were stimulated with the aromatase substrate, androstenedione, with or without the AI anastrozole (Ana). We found that Ana decreased androstenedione-stimulated growth of wild-type cells, whereas K303R-expressing cells were resistant to the inhibitory effect of Ana on growth. We propose that a mechanism of resistance involves an increased binding between the mutant receptor and the p85 regulatory subunit of phosphatidylinositol-3-OH kinase (PI3K), leading to increased PI3K activity and activation of protein kinase B/Akt survival pathways. Inhibition of the selective "addiction" to the PI3K/Akt pathway reversed AI resistance associated with expression of the mutant receptor. Our findings suggest that the K303R ER mutation might be a new predictive marker of response to AIs in mutation-positive breast tumors, and that targeting the PI3K/Akt pathway may be a useful strategy for treating patients with tumors resistant to hormone therapy. [Cancer Res 2009;69(11):4724–32]

 
 
 
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