Abstract
BackgroundChemotherapy is currently one of the most effective treatments for advanced breast cancer. Anti-microtubule agents, including taxanes, eribulin and vinca-alkaloids are one of the primary major anti-breast cancer chemotherapies; however, chemoresistance remains a problem that is difficult to solve. We aimed to discover novel candidate protein targets to combat chemoresistance in breast cancer.MethodsA lentiviral shRNA-based high-throughput screening platform was designed and developed to screen the global kinome to find new therapeutic targets in paclitaxel-resistant breast cancer cells. The phenotypes were confirmed with alternative expression in vitro and in vivo. Molecular mechanisms were investigated using global phosphoprotein arrays and expression microarrays. Global microarray analysis was performed to determine TAOK3 and genes that induced paclitaxel resistance.ResultsA serine/threonine kinase gene, TAOK3, was identified from 724 screened kinase genes. TAOK3 shRNA exhibited the most significant reduction in IC50 values in response to paclitaxel treatment. Ectopic downregulation of TAOK3 resulted in paclitaxel-resistant breast cancer cells sensitize to paclitaxel treatment in vitro and in vivo. The expression of TAOK3 also was correlated to sensitivity to two other anti-microtubule drugs, eribulin and vinorelbine. Our TAOK3-modulated microarray analysis indicated that NF-κB signaling played a major upstream regulation role. TAOK3 inhibitor, CP43, and shRNA of NF-κB both reduced the paclitaxel resistance in TAOK3 overexpressed cells. In clinical microarray databases, high TAOK3 expressed breast cancer patients had poorer prognoses after adjuvant chemotherapy.ConclusionsHere we identified TAOK3 overexpression increased anti-microtubule drug resistance through upregulation of NF-κB signaling, which reduced cell death in breast cancer. Therefore, inhibition of the interaction between TAOK3 and NF-κB signaling may have therapeutic implications for breast cancer patients treated with anti-microtubule drugs.7Jqasva6SWS6RazCnN3hPhVideo abstract
Highlights
Breast cancer is currently the most common cancer among women worldwide as well as the third leading cause of cancer deaths in the United States [1]
Identification of paclitaxel-resistant gene targets in breast cancer cells After evaluating the The half maximal inhibitory concentration (IC50) of paclitaxel in 15 breast cancer cell lines, we found that Au565 was the most paclitaxel-resistant cell line to paclitaxel (Fig. 1a, Table S1)
Many of the identified kinases belonged to the Mitogen-activated protein kinase (MAPK), PI3KAKT, or Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway
Summary
Breast cancer is currently the most common cancer among women worldwide as well as the third leading cause of cancer deaths in the United States [1]. A new generation of anti-microtubule inhibitors, such as eribulin, has shown survival benefits in refractory metastatic breast cancer, which indicates the important role of microtubule-targeted drugs in preventing breast cancer recurrence and controlling progression [3, 4]. The development of new agents to overcome resistance to taxane or other microtubule-targeting drugs is, indispensable to the advancement of disease treatment [11]. Chemotherapy is currently one of the most effective treatments for advanced breast cancer. Antimicrotubule agents, including taxanes, eribulin and vinca-alkaloids are one of the primary major anti-breast cancer chemotherapies; chemoresistance remains a problem that is difficult to solve. We aimed to discover novel candidate protein targets to combat chemoresistance in breast cancer
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