F-box/WD Repeat-Containing Protein 5 Promotes Breast Cancer Progression by Regulating Ferroptosis via Enhancing Krüppel-like Factor 13 Ubiquitination Through Phosphoinositide 3-Kinase/Serine/Threonine Protein Kinase Pathway

Breast cancer (BC) is a prevalent malignancy among women. Evidence has indicated that F-box/WD repeat-containing protein 5 (FBXW5) is crucial in oncogenesis and progression. However, the function of FBXW5 in BC remains elusive. This work aims to explore the regulatory mechanisms of FBXW5 in the development of BC. The expression of FBXW5 in pan-cancer and breast invasive carcinoma (BRCA) was analyzed using The Cancer Genome Atlas (TCGA) database. FBXW5 level was enhanced in BC tissues. Besides, FBXW5 inhibition significantly decreased cell viability by 49.05% in MDA-MB-231 cells and 62.30% in MCF-7 cells. FBXW5 inhibition significantly inhibited cell proliferation by 66% in MDA-MB-231 cells and 74% in MCF-7 cells. FBXW5 inhibition significantly suppressed cell migration by 77.2% in MDA-MB-231 cells and 82.15% in MCF-7 cells. FBXW5 inhibition significantly inhibited cell invasion by 64.14% in MDA-MB-231 cells and 71.33% in MCF-7 cells. In vivo, FBXW5 depletion reduced tumor weight by 63.39% and tumor volume by 65.17%. Moreover, FBXW5 silencing restrained lung metastases in vivo . Besides, the impact of FBXW5 on the malignant behavior of BC cells was mediated through the regulation of ferroptosis. Mechanically, FBXW5 facilitated Kruppel-like factor 13 (KLF13) degradation by enhancing its ubiquitination. The addition of FBXW5 facilitated cell proliferation, migration, and invasion and inhibited ferroptosis in MDA-MB-231 and MCF-7 cells, which were neutralized by KLF13 overexpression. Besides, the knockdown of KLF13 led to the activation of the PI3K/AKT pathway. KLF13 silencing counteracted the inhibitory effects of FBXW5 depletion on cell proliferation, migration, and invasion, as well as its promotion of ferroptosis, effects that were reversed by LY294002. In conclusion, targeting FBXW5 may serve as a potential therapeutic strategy for BC by modulating the KLF13/PI3K/AKT axis.