Abstract
FBXW7 is a component of SCF (complex of SKP1, CUL1 and F-box-protein)-type ubiquitin ligases that targets several oncoproteins for ubiquitination and degradation by the proteasome. FBXW7 regulates cellular apoptosis by targeting MCL1 for ubiquitination. Recently, we identified PLK1 as a new substrate of FBXW7 modulating the intra-S-phase DNA-damage checkpoint. Taxanes are frequently used in breast cancer treatments, but the acquisition of resistance makes these treatments ineffective. We investigated the role of FBXW7 and their substrates MCL1 and PLK1 in regulating the apoptotic response to paclitaxel treatment in breast cancer cells and their expression in breast cancer tissues. Paclitaxel-sensitive MDA-MB-468 and a paclitaxel-resistant MDA-MB-468R subclone were used to study the role of FBXW7 and substrates in paclitaxel-induced apoptosis. Forced expression of FBXW7 or downregulation of MCL1 or PLK1 restored sensitivity to paclitaxel in MDA-MB-468R cells. By contrary, FBXW7-silenced MDA-MB-468 cells became resistant to paclitaxel. The expression of FBXW7 and substrates were studied in 296 invasive carcinomas by immunohistochemistry and disease-free survival was analyzed in a subset of patients treated with paclitaxel. In breast cancer tissues, loss of FBXW7 correlated with adverse prognosis markers and loss of FBXW7 and MCL1 or PLK1 accumulation were associated with diminished disease-free survival in paclitaxel-treated patients. We conclude that FBXW7 regulates the response to paclitaxel by targeting MCL1 and PLK1 in breast cancer cells and thus targeting these substrates may be a valuable adjunct for paclitaxel treatment. Also, FBXW7, MCL1 and PLK1 may be relevant predictive markers of tumor progression and response to paclitaxel treatment.
Highlights
FBXW7 is the F-box protein of the SKP1-CUL1FBXW7 (SCFFBXW7) E3 ubiquitin ligase, responsible for recruiting specific substrates for ubiquitination and degradation by the proteasome [1]
Aurora kinase A (AURKA), c-Myc, Cyclin E, Polo-like kinase 1 (PLK1) and MCL1 levels all increased after FBXW7 downregulation in both cell lines (Figure 1B)
FBXW7 acts as a tumor suppressor involved in the degradation of substrates with oncogenic activity frequently overexpressed in breast cancer such as Cyclin E, c-Myc and AURKA [14, 29,30,31]
Summary
FBXW7 is the F-box protein of the SKP1-CUL1FBXW7 (SCFFBXW7) E3 ubiquitin ligase, responsible for recruiting specific substrates for ubiquitination and degradation by the proteasome [1]. Loss of expression of FBXW7 has been reported in a series of breast carcinomas where Cyclin E was upregulated and associated with poor prognosis [9] but its relationship with other substrates has not been addressed Other substrates such as c-Myc and AURKA have important roles in tumorigenesis by promoting cancer cell survival and migration [10,11,12,13] and AURKA has been found overexpressed in a series of triple negative breast carcinomas [14]. Loss or inactivation of FBXW7 conferred resistance to anti-tubulin agents paclitaxel and vincristine by blocking proteasomal degradation of MCL1 [21]. We identified this important role of MCL1 in preventing cell death during mitosis in prostate cancer cells after paclitaxel treatment [22]. We investigate the role of FBXW7 and relevant substrates in regulating apoptosis induced by paclitaxel in breast cancer cells, their expression in breast cancer tissues, and their potential predictive value in paclitaxel-treated patients
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
