Abstract
BackgroundBreast cancer (BC) remains a prevalent and common form of cancer with high heterogeneity. Making efforts to explore novel molecular biomarkers and serve as potential disease indicators, which is essential to effectively enhance the prognosis and individualized treatment of BC. FBXO proteins act as the core component of E3 ubiquitin ligase, which play essential regulators roles in multiple cellular processes. Recently, research has indicated that FBXOs also play significant roles in cancer development. However, the molecular functions of these family members in BC have not been fully elucidated.MethodsIn this research, we investigated the expression data, survival relevance and mutation situation of 10 FBXO members (FBXO1, 2, 5, 6, 16, 17, 22, 28, 31 and 45) in patients with BC from the Oncomine, GEPIA, HPA, Kaplan–Meier Plotter, UALCAN and cBioPortal databases. The high transcriptional levels of FBXO1 in different subtypes of BC were verified by immunohistochemical staining and the specific mutations of FBXO1 were obtained from COSMIC database. Top 10 genes with the highest correlation to FBXO1 were identified through cBioPortal and COXPRESdb tools. Additionally, functional enrichment analysis, PPI network and survival relevance of FBXO1 and co-expressed genes in BC were obtained from DAVID, STRING, UCSC Xena, GEPIA, bc-GenExMiner and Kaplan–Meier Plotter databases. FBXO1 siRNAs were transfected into MCF-7 and MDA-MB-231 cell lines. Expression of FBXO1 in BC cell lines was detected by western-blot and RT-qPCR. Cell proliferation was detected by using CCK-8 kit and colony formation assay. Cell migration was detected by wound‐healing and transwell migration assay.ResultsWe found that FBXO2, FBXO6, FBXO16 and FBXO17 were potential favorable prognostic factors for BC. FBXO1, FBXO5, FBXO22, FBXO28, FBXO31 and FBXO45 may be the independent poor prognostic factors for BC. All of them were correlated to clinicopathological staging. Moreover, knockdown of FBXO1 in MCF7 and MDA-MB-231 cell lines resulted in decreased cell proliferation and migration in vitro. We identified that FBXO1 was an excellent molecular biomarker and therapeutic target for different molecular typing of BC.ConclusionThis study implies that FBXO1, FBXO2, FBXO5, FBXO6, FBXO16, FBXO17, FBXO22, FBXO28, FBXO31 and FBXO45 genes are potential clinical targets and prognostic biomarkers for patients with different molecular typing of BC. In addition, the overexpression of FBXO1 is always found in breast cancer and predicts disadvantageous prognosis, implicating it could as an appealing therapeutic target for breast cancer patients.
Highlights
Breast cancer (BC) remains a prevalent and common form of cancer with high heterogeneity
The overexpression of FBXO1 is always found in breast cancer and predicts disadvantageous prognosis, implicating it could as an appealing therapeutic target for breast cancer patients
We found that FBXO1, FBXO5, FBXO6, FBXO16, FBXO45 proteins were more highly expressed in the BC tissues than those in the normal tissues
Summary
Breast cancer (BC) remains a prevalent and common form of cancer with high heterogeneity. FBXO proteins act as the core component of E3 ubiquitin ligase, which play essential regulators roles in multiple cellular processes. There is an urgent need to explore novel molecular biomarkers as prognostic indicators in the field of clinical research, which perhaps contribute to improve the prognosis and guide the individualized treatment strategies for BC patients. Ubiquitin proteasome pathway is the most important protein degradation pathway with high selectivity in human, which plays a critical role in tumorigenesis and pathological mechanism of tumor. F-box proteins act as molecular regulators in multiple biological processes of cell like cell cycle, epithelial-mesenchymal transition (EMT), cell apoptosis and many signaling pathways related to tumor such as P13K-AKT-mTOR, p53 and NRF2 [4, 5]. As the largest subfamily of F-box proteins, FBXO has 37 members, it has been verified that many of them are closely related to tumor biological processes according to many studies
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