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Regulation of submaxillary gland androgen regulated protein 3A by estrogen-dependent signaling as a prognostic biomarker in head and neck squamous cell carcinoma

Grünow, Jennifer

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Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. Implementation of interdisciplinary and aggressive treatment regimens have only marginally improved the clinical outcome of patients with advanced HNSCC, which is mainly due to the invasive growth pattern and high rate of therapeutic resistance as a main cause for tumor relapse. Accordingly, unraveling underlying molecular mechanisms and relevant candidate genes as potential drug targets for more efficient and less toxic treatment is eagerly awaited. In the past, induced expression of the mouse homologue of submaxillary Gland androgen regulated protein 3A (SMR3A), a family member of the opiorphin gene family, was identified in a mouse xenograft model of tumor relapse in oral carcinogenesis. More recently, high SMR3A expression was confirmed in a substantial amount of patients with primary oropharyngeal squamous cell carcinoma(OPSCC) and served as an independent risk factor for an unfavorable survival. However, the regulation of SMR3A in treatment resistant tumor cells and its potential role in tumor relevant processes remained elusive and is the major objective of this PhD thesis. First, a cell culture model with ectopic overexpression was established in a HNSCC cell line but did not support a causal link between SMR3A and tumor cell proliferation, migration or adhesion under normal growth conditions. These findings raised the attractive question, whether up-regulation of SMR3A represents a surrogate marker for signaling cascades implicated in treatment resistant of tumor cells. To address this question, several HNSCC cell lines with low basal SMR3A expression were treated with a protocol of fractionated irradiation. Elevated SMR3A expression was a common feature for surviving tumor cells and was accompanied by induced expression of the estrogen receptor 2 (ESR2), suggesting a regulation by activated ESR2 signaling. Indeed, SMR3A could be induced in HNSCC cell lines by estradiol in a time and dose-dependent manner, and estradiol-induced expression was alleviated by co-treatment with either 4-Hydroxytamoxifen or Fulvestrant, two well established inhibitors of ESR2 signaling. The clinical relevance was further validated by a positive staining for ESR2 in tumor cells of primary OPSCC and induced apoptosis of tumor cells after combined treatment with Fulvestrant and fractionated irradiation in vitro.In summary, the presented data strongly support a model in which accelerated SMR3A expression indicates active ESR2 signaling as a key mechanism for survival and clonal evolution of radioresistant tumor cells. As a consequence, HNSCC patients with co-expression of SMR3A and ESR2 in tumor cells prior or during radiotherapy are at high risk for treatment failure, but might benefit from adjuvant therapy with 4-Hydroxytamoxifen or Fulvestrant. However, additional studies in preclinical models are needed as a proof of concept and to pave the way to clinical trials in the future.

Item Type: Dissertation
Supervisor: Angel, Prof. Dr. Peter
Date of thesis defense: 8 June 2016
Date Deposited: 21 Jun 2016 05:11
Date: 2017
Faculties / Institutes: The Faculty of Bio Sciences > Dean's Office of the Faculty of Bio Sciences
Subjects: 610 Medical sciences Medicine
Controlled Keywords: head and neck squamous cell carcinoma, SMR3A, estrogen receptor signaling, radiotherapy
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