CYLD 発現低下による予後不良トリプルネガティブ型乳癌に対するNF-κB シグナルを標的とした新規薬物治療

• Published in: 日本薬理学会年会要旨集 p. 3-B-O14-4
• Main Authors: 新垣, ひとみ, 桑野, 明香里, 平井, ちか, 西郷, 智香, 金丸, 歩美, 林, 光博, 齋藤, 秀之, 成田, 勇樹, 城野, 博史
• Format: Journal Article
• Language: Japanese
• Published: 公益社団法人 日本薬理学会 2023
• Subjects: cancer; drug efficacy
• ISSN: 2435-4953
• DOI: 10.1254/jpssuppl.97.0_3-B-O14-4

【INTRODUCTION】Triple negative breast cancer (TNBC) is the most aggressive form of breast cancer. Since TNBC exhibits a significantly lower 5-year survival rate than other subtypes, development of novel therapeutic strategies for TNBC is urgently needed. Tumor suppressor gene Cylindromatosis (CYLD) is associated with acquisition of malignant traits in various malignant tumors as a negative regulator for intracellular signals, such as nuclear factor-κB (NF-κB) signaling. The aim of this study was to clarify the clinical and biological significance of reduced CYLD expression in TNBC and to explore novel pharmacotherapy CYLD-negative poor-prognosis TNBC patients.【METHODS】We knocked-downed CYLD expression by CYLD-specific siRNA in TNBC cells (MDA-MB-231 cells), and determined the therapeutic effects of anti-tumor drugs by evaluating malignant characteristics, such as, migration ability and anticancer drug sensitivity.  【RESULTS】In CYLD knock-downed TNBC cells, cell migration and drug resistance for epirubicin and 5-FU, standard drugs for TNBC, were promoted via hyper-activation of NF-kB signaling. Indeed, NF-kB inhibitor (BAY11-7085) significantly suppressed the cell migration and cell viability caused by CYLD knock-down. Furthermore, therapeutic effects of clinically approved NF-kB inhibitors, such as, denosumab and bortezomib, were evaluated in CYLD knock-downed TNBC cells. In addition to the therapeutic effect of denosumab on cell migration, interestingly, bortezomib showed significant inhibitory effect on both cell viability and cell migration. 【DISCUSSION】Loss of CYLD expression enhanced the cell migration and drug resistance through hyper-activation of NF-kB signaling. Both clinically approved NF-kB inhibitors exhibited therapeutic effects, in particular, bortezomib might be more effective for TNBC cells with loss of CYLD expression by suppressing both cell viability and cell migration.【CONCLUSION】Pharmacotherapy targeting NF-kB signaling may have potential to be novel therapeutic strategy for poor prognosis TNBC patients with loss of CYLD expression.