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@ARTICLE{Grnow:120527,
      author       = {J. Grünow$^*$ and C. Rong and J. Hischmann and K. Zaoui
                      and C. Flechtenmacher and K.-J. Weber and P. Plinkert and J.
                      Hess$^*$},
      title        = {{R}egulation of submaxillary gland androgen-regulated
                      protein 3{A} via estrogen receptor 2 in radioresistant head
                      and neck squamous cell carcinoma cells.},
      journal      = {Journal of experimental $\&$ clinical cancer research},
      volume       = {36},
      number       = {1},
      issn         = {1756-9966},
      address      = {Berlin},
      publisher    = {Springer},
      reportid     = {DKFZ-2017-00956},
      pages        = {25},
      year         = {2017},
      abstract     = {Molecular mechanisms of intrinsic or acquired
                      radioresistance serve as critical barrier for curative
                      therapy of head and neck squamous cell carcinoma (HNSCC) and
                      remain a major obstacle for progression-free and
                      disease-specific survival.HNSCC cell lines were treated with
                      a protocol of fractionated irradiation (IR, 4× 2Gy) alone
                      or in combination with antagonists of estrogen receptor
                      signaling and viability was determined by a colony-forming
                      assay (CFA). Expression of submaxillary gland
                      androgen-regulated protein 3A (SMR3A) and estrogen receptor
                      2 (ESR2) were assessed in tumor cells in vitro by RQ-PCR,
                      Western blot analysis and immunofluorescence staining, and
                      by immunohistochemical staining of tissue microarrays
                      containing tumor sections from patients with oropharyngeal
                      squamous cell carcinoma (OPSCC), which were treated by
                      definitive or adjuvant radiotherapy. Subgroups with distinct
                      SMR3A and ESR2 expression patterns were correlated with
                      clinical parameters and survival outcome including
                      multivariable analysis.Fractionated irradiation (IR)
                      revealed an accumulation of tumor cells with prominent SMR3A
                      expression, which was accompanied by an up-regulation of the
                      estrogen receptor 2 (ESR2). ESR2-dependent regulation of
                      SMR3A was supported by induced expression after stimulation
                      with estradiol (E2), which was impaired by co-treatment with
                      4-Hydroxytamoxifen (TAM) or Fulvestrant, respectively. Both
                      drugs significantly sensitized FaDu cells to fractionated IR
                      as determined by a CFA and accelerated apoptosis. These data
                      suggest a critical role of ESR2 in radioresistance and that
                      SMR3A might serve as a surrogate marker for active ESR2
                      signaling. In line with this assumption, ESR2-positive
                      oropharyngeal squamous cell carcinoma (OPSCC) with high
                      SMR3A expression had an unfavorable progression-free and
                      disease-specific survival as compared to those tumors with
                      low SMR3A expression.In summary, our findings provide
                      compelling experimental evidence that HNSCC with SMR3A and
                      ESR2 co-expression have a higher risk for treatment failure
                      and these patients might benefit from clinically
                      well-established drugs targeting estrogen receptor
                      signaling.},
      cin          = {G405},
      ddc          = {610},
      cid          = {I:(DE-He78)G405-20160331},
      pnm          = {317 - Translational cancer research (POF3-317)},
      pid          = {G:(DE-HGF)POF3-317},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:28166815},
      pmc          = {pmc:PMC5294868},
      doi          = {10.1186/s13046-017-0496-2},
      url          = {https://inrepo02.dkfz.de/record/120527},
}