ABSTRACT
ABSTRACT: System paclitaxel-based chemotherapy is the first-line treatment regimen of defense against breast cancer, but inherent or acquired chemotherapy resistance remains a major obstacle in breast cancer therapy. Elucidating the molecular mechanism of chemoresistance is essential to improve the outcome of patients with breast cancer. Here, we demonstrate that intraflagellar transport 20 (IFT20) is positively associated with shorter relapse-free survival in patients with system paclitaxel-based chemotherapy. High-expressed IFT20 in breast cancer cells increases resistance to cell death upon paclitaxel treatment; in contrast, IFT20 knockdown enhances apoptosis in breast cancer cells in response to paclitaxel. Mechanistically, IFT20 triggers ß-arrestin-1 to bind with apoptosis signal-regulating kinase 1 (ASK1) and promotes the ubiquitination of ASK1 degradation, leading to attenuating ASK1 signaling and its downstream JNK cascades, which helps cells to escape from cell death during paclitaxel treatment. Our results reveal that IFT20 drives paclitaxel resistance through modulating ASK1 signaling and identifies IFT20 as a potential molecular biomarker for predicting the response to paclitaxel therapeutic in breast cancer. IMPLICATIONS: IFT20 drives paclitaxel resistance through modulating ASK1 signaling and IFT20 may act as a potential molecular biomarker for predicting the response to paclitaxel therapeutic in breast cancer.
Subject(s)
Breast Neoplasms , Paclitaxel , Humans , Female , Paclitaxel/pharmacology , Paclitaxel/therapeutic use , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , beta-Arrestin 1/genetics , beta-Arrestin 1/metabolism , beta-Arrestin 1/therapeutic use , MAP Kinase Kinase Kinase 5/genetics , MAP Kinase Kinase Kinase 5/metabolism , MAP Kinase Kinase Kinase 5/therapeutic use , Cell Line, Tumor , Neoplasm Recurrence, Local/drug therapy , Apoptosis , Drug Resistance, Neoplasm , Carrier ProteinsABSTRACT
Patients with Her2-positive breast cancer exhibit de novo resistance or develop acquired resistance in less than one year after Her2 targeting treatment, but the mechanism is not fully elucidated. Compensatory pathways such as the IGF-1R/IRS-1 pathway, are activated, leading to aberrant enhanced PI3K/Akt/mTOR pathway activity to attenuate the efficacy of trastuzumab. Cullin7 could participate in the degradation of IRS-1 in a mTOR/S6K dependent manner. Whether Cullin7 participates in trastuzumab resistance needs to be further investigated. Here, we reveals that Cullin7 is overexpressed in trastuzumab-resistant Her2 positive breast cancer cells. Knockdown of Cullin7 reduces degradation of Ser phosphorylation of IRS-1, attenuates activation of the PI3K/AKT pathway, and partly restores trastuzumab sensitivity in trastuzumab-resistant Her2 positive breast cancer cells. IGFBP-3 expression is decreased in trastuzumab-resistant Her2 positive breast cancer cells, which leads to release of the Wnt signaling pathway inhibition and an increase in Cullin7 expression, as mediated by TCF7L2. Overexpression of Cullin7 in Her2-amplified breast cancer tissues has clinical implications because it positively correlates with shorter disease-free survival (DFS) and inadequate response to trastuzumab. Thus, our results suggest a critical role for Cullin7 in response to trastuzumab, which has significant implications for selection of the optimal therapeutic strategy for Her2 positive breast cancers.
