Systematic analysis reveals that KCNH8 suppresses triple-negative breast cancer progression through PI3K‑AKT inhibition

Abstract

Among women, tripple-negative breast cancer (TNBC) is highly prevalent, and controlling recurrence and metastatic disease remains difficult in clinical practice. The potassium channel KCNH8 shows dysregulated expression across multiple cancers; however, its roles and underlying mechanisms in the context of breast carcinoma have yet to be clarified. In this study, we explored the expression, prognosis, methylation status, and immune infiltration features of KCNH8 using GEO and TCGA databases. We investigated the impact of KCNH8 expression levels on the biological behaviors of TNBC cells using in vitro cellular phenotype assays and immunoblot assays. Tumorigenicity in vivo was examined with subcutaneous xenografts established in nude mice. KCNH8 expression was reduced in breast tumors, and higher levels were linked to improved overall survival and more favorable clinicopathologic characteristics. KCNH8 methylation was elevated and negatively correlated with KCNH8 expression. Functionally, elevating KCNH8 curtailed proliferation, migration, invasion, and EMT, whereas depletion enhanced these malignant traits. Mechanistically, KCNH8 reduced PI3K/AKT phosphorylation, and pharmacologic activation of PI3K partly counteracted its growth‑suppressive effects. In mouse models, enforced KCNH8 expression restrained tumor growth. Overall, KCNH8 is reduced in breast carcinoma, and it could inhibit tumor progression by suppressing PI3K/AKT pathway activity. These findings support KCNH8 as a candidate marker for prognostic assessment.