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Kammerer, S.
Validation of G-protein coupled inwardly rectifying potassium channel 1 (GIRK1) as new prognostic breast cancer biomarker
Doktoratsstudium der Medizinischen Wissenschaft; Humanmedizin; [ Dissertation ] Graz Medical University; 2016. pp. 100 [OPEN ACCESS]
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Authors Med Uni Graz:
Advisor:
Bauernhofer Thomas
Jahn Stephan
Schreibmayer Wolfgang
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Abstract:
It has been shown in several studies that potassium channels are involved in tumor development and metastasis. Amongst them, GIRK1 has been found to correlate with lymph node metastasis in breast cancer patients and to be elevated in breast tumors when compared to normal breast tissue. The study of potential new biomarkers for distinct cancer types is crucial for the improvement of patient diagnosis, treatment and outcome. Therefore, the aim of this project was to study GIRK1 expression levels first in the publicly available data set of The Cancer Genome Atlas (TCGA) to derive important information on expression patterns in different breast cancer subsets; second, to establish methods for the detection of GIRK1 in human formalin-fixed, paraffin-embedded (FFPE) breast cancer tissue; and third, to validate the findings of the TCGA in a well characterized cohort of FFPE breast cancer samples. Analysis of the TCGA showed a strong correlation between GIRK1 and estrogen receptor (ER) expression levels (p<0.001). Correlation and/or association with other clinical features such as tumor size, lymph node and metastasis status, tumor grade, histology, Her2 status or age at diagnosis were not significant. GIRK1 levels were, despite the strong correlation, variable within the ER positive subgroup and survival analysis showed that ER positive patients with high GIRK1 expression had worse overall survival probabilities than the ones with low GIRK1 levels (HR=1.77 (1.04-3.02); p<0.05). A multivariate analysis showed that GIRK1 was an independent prognostic marker for ER positive breast cancer patients (HR=5.2 (1.3-21.8; p<0.05), being also independent of the PAM50 status. We then established protocols for GIRK1 immunohistochemistry and RNA in situ hybridization (ISH), whereby the ISH method was more robust, sensitive and specific and was therefore selected for further use on ER positive patient samples. The results of the validation set confirmed the previous findings, showing again that ER positive patients had both worse disease free (HR=3.1 (1.3-7.6) p<0.01) and overall survival (HR=2.4 (1.2-4.8); p<0.05) probabilities when GIRK1 levels in the tumor were high. We conclude that GIRK1 might become a prognostic biomarker for ER positive breast cancer and provide a diagnostic tool for the detection of GIRK1 in FFPE tissue (RNA ISH). Further studies will elucidate the molecular mechanisms that lead to GIRK1 upregulation in breast cancer and give insights into involved signaling pathways.

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