Abstract
BackgroundCentromere Protein F (CENPF) associates with the centromere–kinetochore complex and influences cell proliferation and metastasis in several cancers. The role of CENPF in breast cancer (BC) bone metastasis remains unclear.MethodsUsing the ONCOMINE database, we compared the expression of CENPF in breast cancer and normal tissues. Findings were confirmed in 60 BC patients through immunohistochemical (IHC) staining. Microarray data from GEO and Kaplan–Meier plots were used analyze the overall survival (OS) and relapse free survival (RFS). Using the GEO databases, we compared the expression of CENPF in primary lesions, lung metastasis lesions and bone metastasis lesions, and validated our findings in BALB/C mouse 4T1 BC models. Based on gene set enrichment analysis (GSEA) and western blot, we predicted the mechanisms by which CENPF regulates BC bone metastasis.ResultsThe ONCOMINE database and immunohistochemical (IHC) showed higher CENPF expression in BC tissue compared to normal tissue. Kaplan–Meier plots also revealed that high CENPF mRNA expression correlated to poor survival and shorter progression-free survival (RFS). From BALB/C mice 4T1 BC models and the GEO database, CENPF was overexpressed in primary lesions, other target organs, and in bone metastasis. Based on gene set enrichment analysis (GSEA) and western blot, we predicted that CENPF regulates the secretion of parathyroid hormone-related peptide (PTHrP) through its ability to activate PI3K–AKT–mTORC1.ConclusionCENPF promotes BC bone metastasis by activating PI3K–AKT–mTORC1 signaling and represents a novel therapeutic target for BC treatment.
Highlights
Centromere Protein F (CENPF) associates with the centromere–kinetochore complex and influences cell proliferation and metastasis in several cancers
CENPF is overexpressed in breast and lung cancer From ONCOMINE analysis, CENPF mRNA expression was significantly higher in breast cancer (BC) samples across the 14 datasets in different cancer types (Table 1 and Fig. 1a, b)
To further determine the role of CENPF in BC, 60 BC samples and paired normal tissue were collected and assessed by immunohistochemistry (IHC) staining. This confirmed that CENPF is expressed to higher levels in BC (42/60, 70%) compared to normal tissues (20/60, 33.3%) (p < 0.01) (Fig. 3a, b)
Summary
Centromere Protein F (CENPF) associates with the centromere–kinetochore complex and influences cell proliferation and metastasis in several cancers. The role of CENPF in breast cancer (BC) bone metastasis remains unclear. Breast cancer (BC) remains a leading cause of cancer related death in women across the globe [1]. The disease enters an incurable stage, with a median survival time of only 2 years, and 5-year survival rates of 20% [5,6,7,8]. Controlling bone metastasis in breast cancer remains a problem in clinical practice. Bone metastasis is a complex, multistage process that includes local invasion, intravasation, survival in the circulation, extravasation, and colonization [9, 10]. An array of pathogenic molecules mediate BC bone metastasis including parathyroid hormone-related protein (PTHrP), interleukin 8 (IL-8), and vascular cell adhesion molecule
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