The Role of FBXW7 in Gynecologic Malignancies

Abstract

The F-Box and WD Repeat Domain Containing 7 (FBXW7) protein has been shown to regulate cellular growth and act as a tumor suppressor. This protein, also known as FBW7, hCDC4, SEL10 or hAGO, is encoded by the gene FBXW7. It is a crucial component of the Skp1-Cullin1-F-box (SCF) complex, which is a ubiquitin ligase. This complex aids in the degradation of many oncoproteins, such as cyclin E, c-JUN, c-MYC, NOTCH, and MCL1, via the ubiquitin-proteasome system (UPS). The FBXW7 gene is commonly mutated or deleted in numerous types of cancer, including gynecologic cancers (GCs). Such FBXW7 mutations are linked to a poor prognosis due to increased treatment resistance. Hence, detection of the FBXW7 mutation may possibly be an appropriate diagnostic and prognostic biomarker that plays a central role in determining suitable individualized management. Recent studies also suggest that, under specific circumstances, FBXW7 may act as an oncogene. There is mounting evidence indicating that the aberrant expression of FBXW7 is involved in the development of GCs. The aim of this review is to give an update on the role of FBXW7 as a potential biomarker and also as a therapeutic target for novel treatments, particularly in the management of GCs.

Targeted variant prevalence of FBXW7 gene mutation in colorectal carcinoma propagation. The first systematic review and meta-analysis

“…Nevertheless, the prevalence and occurrence of FBXW7 mutations differs as reported in published data; approximately cholangiocarcinoma (15 %) [ 85 ], T-cell acute lymphocytic leukemia T-ALL (31 %) [ 86 ], cancer of the bladder (10 %) [ 5 ], gastrinoma carcinoma (6 %), squamous cell cancer of the lungs (5 %) [ 87 ], endometrial carcinoma (16 %), ovarian cancer (8.3 %) [ 88 ] etc. Overall, CRC comprises of 4.2 % of all cancer's new cases [ 89 ], been the third most in both predominancy and occurring cause of cancer death around the world [ 89 , 90 ], CRC is responsible for approximately one million deaths and newfound cases of about 1.91 million in 2018 [ 91 ].…”

Targeted and Shallow Whole-Genome Sequencing Identifies Therapeutic Opportunities in p53abn Endometrial Cancers

“…Furthermore, tumors with genetic alterations in FBXW7 and PPP2R1A could benefit from PKMYT1 inhibition. The FBXW7 tumor suppressor is part of a ubiquitin–ligase complex that degrades CCNE1 ; therefore, mutations affecting the ubiquitination process or CN loss at the FBXW7 locus results in accumulation of CCNE1 , phenocopying CCNE1 amplification ( 42 ). Similarly, the PPP2R1A tumor suppressor, a component of the PP2A phosphatase complex, causes dephosphorylation and degradation of CCNE1 ; and loss-of-function mutations in PPP2R1A causes CCNE1 accumulation ( 43 ).…”

Comparative analysis of EZH2, p16 and p53 expression in uterine carcinosarcomas

“…Mutations in TP53 are frequently observed across various tumors, underscoring the pivotal involvement of the FBXW7, p53, and PI3K pathways in UCS. Among these pathways, FBXW7 stands out as a crucial driver in the development of this particular cancer [ 88 ]. Conclusive genetic evidence obtained through lineage tracing studies indicates that UCS originates from endometrial epithelial cells undergoing an epithelial-mesenchymal transition.…”