Abstract
Numerous studies showed abnormal expression of ion channels in different cancer types. Amongst these, the potassium channel gene KCNJ3 (encoding for GIRK1 proteins) has been reported to be upregulated in tumors of patients with breast cancer and to correlate with positive lymph node status. We aimed to study KCNJ3 levels in different breast cancer subtypes using gene expression data from the TCGA, to validate our findings using RNA in situ hybridization in a validation cohort (GEO ID GSE17705), and to study the prognostic value of KCNJ3 using survival analysis. In a total of > 1000 breast cancer patients of two independent data sets we showed a) that KCNJ3 expression is upregulated in tumor tissue compared to corresponding normal tissue (p < 0.001), b) that KCNJ3 expression is associated with estrogen receptor (ER) positive tumors (p < 0.001), but that KCNJ3 expression is variable within this group, and c) that ER positive patients with high KCNJ3 levels have worse overall (p < 0.05) and disease free survival probabilities (p < 0.01), whereby KCNJ3 is an independent prognostic factor (p <0.05). In conclusion, our data suggest that patients with ER positive breast cancer might be stratified into high risk and low risk groups based on the KCNJ3 levels in the tumor.
Highlights
Human G-protein activated inward rectifier potassium channel subunits (GIRKs) are encoded by four genes (KCNJ3; KCNJ5; KCNJ6; KCNJ9)
In a total of > 1000 breast cancer patients of two independent data sets we showed a) that KCNJ3 expression is upregulated in tumor tissue compared to corresponding normal tissue (p < 0.001), b) that KCNJ3 expression is associated with estrogen receptor (ER) positive tumors (p < 0.001), but that KCNJ3 expression is variable within this group, and c) that ER positive patients with high KCNJ3 levels have worse overall (p < 0.05) and disease free survival probabilities (p < 0.01), whereby KCNJ3 is an independent prognostic factor (p
Ko et al [33] performed ion channel profiling in breast cancer and mentioned a decrease of KCNJ3 expression in p53 mutant breast tumors, which are more likely to be ER negative [34], and an increase in KCNJ3 mRNA expression in ER positive tumors when compared to ER negative samples
Summary
Human G-protein activated inward rectifier potassium channel subunits (GIRKs) are encoded by four genes (KCNJ3; KCNJ5; KCNJ6; KCNJ9). Functional roles of KCNJ3 expression in breast cancer were investigated by Rezania et al [13], who demonstrated that stable overexpression of KCNJ3 in MCF-7 breast cancer cells results in increased motility, invasiveness and angiogenesis compared to controls. Based on these results, we intended to study and validate KCNJ3 expression in invasive breast carcinoma samples as potential new prognostic biomarker. Our results suggest that KCNJ3 upregulation is an independent prognostic factor for estrogen receptor positive breast cancer
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