FBXW7 in breast cancer: mechanism of action and therapeutic potential

Abstract

Breast cancer is one of the frequent tumors that seriously endanger the physical and mental well-being in women. F-box and WD repeat domain-containing 7 (FBXW7) is a neoplastic repressor. Serving as a substrate recognition element for ubiquitin ligase, FBXW7 participates in the ubiquitin–proteasome system and is typically in charge of the ubiquitination and destruction of crucial oncogenic proteins, further performing a paramount role in cell differentiation, apoptosis and metabolic processes. Low levels of FBXW7 cause abnormal stability of pertinent substrates, mutations and/or deletions in the FBXW7 gene have been reported to correlate with breast cancer malignant progression and chemoresistance. Given the lack of an effective solution to breast cancer's clinical drug resistance dilemma, elucidating FBXW7's mechanism of action could provide a theoretical basis for targeted drug exploration. Therefore, in this review, we focused on FBXW7's role in a range of breast cancer malignant behaviors and summarized the pertinent cellular targets, signaling pathways, as well as the mechanisms regulating FBXW7 expression. We also proposed novel perspectives for the exploitation of alternative therapies and specific tumor markers for breast cancer by therapeutic strategies aiming at FBXW7.

MYCN in human development and diseases

“…Noteworthy, the growing evidence of the therapeutic approaches is proposed in terms of the treatment for MYCN-associated tumors, which targets MYCN transcription, stability, MYCN cofactors/ coregulators and MYCN downstream targets (121). In addition, the investigations targeting hedgehog signaling, cyclin D, and FBXW7 are also under development (122)(123)(124)(125). Though its relative difficulty for application to developmental disease due to the more intricate adjustment during development, not only quantitatively but also geographically, this oncologic knowledge might contribute to the development of therapeutic approaches even to the developmental disorders discussed in this review.…”

Fbxw7 suppresses carcinogenesis and stemness in triple-negative breast cancer through CHD4 degradation and Wnt/β-catenin pathway inhibition

“…FBXW7 primarily targets oncoproteins for degradation and is thus widely recognized as a classic tumor suppressor gene. Previous studies on breast cancer have shown that the mutation frequency of FBXW7 in TNBC is considerably higher than that in ER receptor-positive BC [ 19 ]. It has also been observed that FBXW7 plays a role in ubiquitinating and degrading EglN2, thereby inhibiting TNBC tumorigenesis [ 20 ].…”

Identifying novel circadian rhythm biomarkers for diagnosis and prognosis of melanoma by an integrated bioinformatics and machine learning approach

“…FBXW7 also inhibits the MITF/PGC-1α pathway, thereby suppressing melanoma cell proliferation relying on mitochondrial oxidative metabolism [43]. Downregulation of FBXW7 has been observed in breast, gastric and pancreatic cancers, where its low expression associates with unfavorable prognosis [44][45][46]. As in melanoma, FBXW7 exhibits anti-tumor activities in other cancers by regulating oncogenes such as c-Myc and p53 [47,48].…”