Department of Oncology and Hematology, Yan'an People's Hospital, Yan'an City, Shaanxi Province, China.
Department of Thyroid and Breast Surgery, The Second People's Hospital of Nantong, Nantong City, Jiangsu Province, China.
Drug Dev Res. 2022 Feb;83(1):208-216. doi: 10.1002/ddr.21860. Epub 2021 Aug 4.
Breast cancer (BC), which is widely considered as the most common cancer in women around the world, evokes ~1.7 million new BC cases and 522,000 BC-related deaths each year. Triple negative breast cancer (TNBC) is clinically confirmed as one of the most aggressive subtypes of BC. ORY-1001, a clinically used lysine specific demethylase 1 (LSD1/KDM1A) inhibitor, was investigated herein to confirm its role in the progression of TNBC and reveal the potential mechanism. After treatment with ORY-1001 in MDA-MB-231 and BT549 cells, the cell proliferation and apoptosis were respectively measured by CCK-8 and TUNEL assays. The expression of proliferation- and apoptosis-associated proteins was tested by means of western blot analysis. Then, R1881, an androgen receptor (AR) agonist, was used to evaluate whether the effects of ORY-1001 on proliferation and apoptosis of TNBC cells was mediated by regulating AR. Results indicated that ORY-1001 treatment restrained the proliferation while enhanced the apoptosis of BC cells, accompanied by the change of proliferation- and apoptosis-related proteins expression. Furthermore, ORY-1001 reduced the level of AR in BC cells. After the activation of AR by R1881, the decreased proliferation and enhanced apoptosis of BC cells triggered by ORY-1001 intervention were partially abolished. In conclusion, this paper has presented the first evidence to suggest that ORY-1001 inhibits proliferation and promotes apoptosis of TNBC cells by suppressing AR expression, which may constitute the theoretical basis for the clinical use of ORY-1001 in the treatment of this disease.
乳腺癌（BC）被广泛认为是全世界女性最常见的癌症，每年引发约 170 万例新的 BC 病例和 52.2 万例与 BC 相关的死亡。三阴性乳腺癌（TNBC）被临床确认为 BC 最具侵袭性的亚型之一。ORY-1001 是一种临床使用的赖氨酸特异性去甲基化酶 1（LSD1/KDM1A）抑制剂，本文旨在研究其在 TNBC 进展中的作用，并揭示其潜在机制。ORY-1001 处理 MDA-MB-231 和 BT549 细胞后，分别通过 CCK-8 和 TUNEL 检测细胞增殖和凋亡。通过 Western blot 分析检测增殖和凋亡相关蛋白的表达。然后，使用雄激素受体（AR）激动剂 R1881 来评估 ORY-1001 对 TNBC 细胞增殖和凋亡的影响是否通过调节 AR 介导。结果表明，ORY-1001 处理抑制了 BC 细胞的增殖，同时增强了其凋亡，伴随着增殖和凋亡相关蛋白表达的变化。此外，ORY-1001 降低了 BC 细胞中的 AR 水平。用 R1881 激活 AR 后，ORY-1001 干预引起的 BC 细胞增殖减少和凋亡增强部分被消除。总之，本文首次提供了证据表明，ORY-1001 通过抑制 AR 表达来抑制 TNBC 细胞的增殖并促进其凋亡，这可能为 ORY-1001 在该疾病治疗中的临床应用提供理论依据。
