三阴性乳腺癌奥拉帕利疗效新靶点
学术
健康
2025-01-22 16:26
上海
三阴性乳腺癌是乳腺癌的特殊亚型，雌激素受体、孕激素受体、人类表皮生长因子受体HER2均为阴性，对传统的内分泌治疗和HER2靶向治疗不敏感，是乳腺癌临床治疗的难点和瓶颈，全身治疗主要依靠化疗。然而，不到30%的三阴性乳腺癌患者标准化疗后完全缓解。令人鼓舞的是，多腺苷二磷酸核糖聚合酶（PARP）抑制剂等新型靶向药物正在扩大三阴性乳腺癌的治疗选择。不过，大多数患者对PARP抑制剂原发耐药或者长期治疗后继发耐药。因此，确定新的生物标志物以选择最有可能对PARP抑制剂治疗获益患者并发现三阴性乳腺癌治疗新靶点至关重要。 2025年1月21日，德国《先进科学》在线发表复旦大学附属肿瘤医院黄敏莹①、蔡嘉洋①、杨绍英、赵谦、邵志敏、张方淋✉️、张银玲✉️、曹阿勇✉️、李大强✉️等学者的研究报告，首次发现此前对人类癌症作用尚不明确的基因SCRN2可以抑制三阴性乳腺癌进展，而且无论在体外还是在体内都可以增强对PARP抑制剂奥拉帕利的敏感性。SCRN是蛋白质Secernin家族编码基因，该家族包括SCRN1、SCRN2和SCRN3。此前对SCRN的研究主要集中于SCRN1和SCRN3，目前全世界已经发表的SCRN2研究报告仅5篇，而且主要针对动物或人类非癌症疾病。 该研究首先对复旦大学附属肿瘤医院和临床蛋白质组学肿瘤分析联盟的三阴性乳腺癌蛋白质组学数据集进行分析，首次发现三阴性乳腺癌患者SCRN2表达水平显著较低，与高表达患者相比，无复发生存率和无远处转移生存率显著较低。 在三阴性乳腺癌中，SCRN2主要被蛋白质分子伴侣介导的自噬作用降解。此外，SCRN2通过凋亡抑制因子Bcl2相关基因BAG2可以阻断组蛋白赖氨酸N-甲基转移酶2C（KMT2C）蛋白酶体降解作用，从而阻断KMT2C与泛素连接酶CHIP的相互作用。同样，SCRN2通过扩增其增强子赖氨酸4组蛋白H3单甲基化转录激活Bcl2修饰因子，从而诱发细胞凋亡。值得注意的是，无论在体外还是在体内，抑制KMT2C基因表达可以恢复SCRN2过表达所致三阴性乳腺癌进展。此外，SCRN2可以降低关键DNA修复相关基因表达并且诱发内源性DNA损伤，从而增强三阴性乳腺癌细胞对奥拉帕利的敏感性。 因此，该研究表明，SCRN2通过稳定KMT2C可以抑制三阴性乳腺癌进展，并且增强对奥拉帕利的敏感性，有望成为三阴性乳腺癌对奥拉帕利耐药的新靶点，对于三阴性乳腺癌的靶向治疗具有潜在作用，故有必要进一步开展大样本前瞻临床研究进行验证。Adv Sci (Weinh). 2025 Jan 21. IF: 14.3Secernin-2 Stabilizes Histone Methyltransferase KMT2C to Suppress Progression and Confer Therapeutic Sensitivity to PARP Inhibition in Triple-Negative Breast Cancer.Min-Ying Huang, Jia-Yang Cai, Shao-Ying Yang, Qian Zhao, Zhi-Min Shao, Fang-Lin Zhang, Yin-Ling Zhang, A-Yong Cao, Da-Qiang Li.Shanghai Cancer Center and Institutes of Biomedical Sciences and Cancer Institute, Shanghai Medical College, Fudan University, Shanghai, China.Triple-negative breast cancer (TNBC) is a difficulty and bottleneck in the clinical treatment of breast cancer due to a lack of effective therapeutic targets. Herein, we first report that secernin 2 (SCRN2), an uncharacterized gene in human cancer, acts as a novel tumor suppressor in TNBC to inhibit cancer progression and enhance therapeutic sensitivity to poly(ADP-ribose) polymerase (PARP) inhibition both in vitro and in vivo. SCRN2 is downregulated in TNBC through chaperone-mediated autophagic degradation, and its downregulation is associated with poor patient prognosis. Moreover, SCRN2 impedes the proteasomal degradation of histone-lysine N-methyltransferase 2C (KMT2C) by recruiting Bcl2-associated athanogene 2 to block the interaction of KMT2C with E3 ubiquitin-protein ligase CHIP. Consistently, SCRN2 transcriptionally activates Bcl2-modifying factor by amplifying histone H3 monomethylation at lysine 4 at its enhancer, thereby inducing intrinsic apoptosis. Notably, KMT2C knockdown restores the impaired TNBC progression caused by SCRN2 overexpression both in vitro and in vivo. Furthermore, SCRN2 decreases the expression of key DNA repair-related genes and induces endogenous DNA damage, thus conferring therapeutic sensitivity of TNBC cells to PARP inhibition. Collectively, these findings identify SCRN2 as a novel suppressor of TNBC, reveal its mechanism of action, and highlight its potential role in TNBC therapy.DOI: 10.1002/advs.202413280
