Purpose: Spindle and kinetochore‑associated complex subunit 3 (SKA3) has recently been identified as a novel regulator of carcinogenesis in multiple types of cancers. However, the function and potential regulatory mechanisms of SKA3 in breast cancer remain poorly understood. The present study was designed to gain a detailed relevance of SKA3 in breast cancer.
Methods: Expression of SKA3 in breast cancer was examined via real-time quantitative PCR, western blotting and immunohistochemistry analysis. Malignant behaviors of breast cancer cells were investigated via cell counting kit-8, cell apoptosis, and transwell invasion assays. The activity of Wnt/β-catenin signaling was monitored via luciferase reporter assay. The tumorigenicity of breast cancer cells in vivo was assessed via xenograft tumor assay.
Results: SKA3 expression was elevated in breast cancer tissue and was correlated with shorter survival rates in breast cancer patients. Knockdown of SKA3 caused marked reductions in cellular proliferation and invasion in breast cancer cells, whereas SKA3 overexpression accelerated proliferation and invasion. Knockdown of SKA3 resulted in decreased Akt and glycogen synthase kinase-3β phosphorylation, and decreased expression of active β-catenin, which lead to the inactivation of Wnt/β-catenin signaling. Inhibition of Akt significantly reversed the SKA3 overexpression-induced activation of Wnt/β-catenin signaling. Inhibition of Wnt/β-catenin signaling markedly abrogated SKA3 overexpression-induced tumor-promotion effects, while re-activation of Wnt/β-catenin signaling significantly reversed SKA3 knockdown-mediated tumor-inhibition effects. Knockdown of SKA3 resulted in a significant decrease in breast cancer tumor formation in vivo.
Conclusions: SKA3 accelerates proliferation and invasion in breast cancer through the modulation of Akt/Wnt/β-catenin signaling.
Keywords: Akt; Breast cancer; GSK-3β; SKA3; Wnt.