PO.CL12.02 · 临床研究

抑制MAGED1增加BRCA突变乳腺癌细胞对PARP抑制剂的敏感性

Suppression of MAGED1 increases sensitivity to PARP inhibitor in BRCA-mutated breast cancer cells

编号 7918 展板 23 时间 4/22 09:00–12:00 区域 Section 48 主讲 In Hee Lee, MD;PhD

分会场 Translational Biomarkers and Emerging Molecular Approaches

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作者与单位 Authors & Affiliations

In Hee Lee, Soo Jung Lee, Byeongju Kang, Jeeyeon Lee, Ho Yong Park, Joon Suk Moon, Ji-Young Park, Yee Soo Chae, Eun Ae Kim, Seol-Hwa Jeong, Jieun Kang

Kyungpook National Chilgok University Hospital, Daegu, Korea, Republic of

摘要 Abstract

中文摘要

背景：MAGED1（黑色素瘤抗原基因家族成员D1）是MAGE基因家族的成员，已知参与多种细胞过程，如细胞死亡、细胞周期调控和分化。此外，先前研究表明MAGED1对通过同源重组修复（HRR）进行的双链断裂（DSB）修复至关重要，MAGED1表达降低使癌细胞对DNA损伤剂敏感。本研究旨在探究MAGED1在三阴性乳腺癌（TNBC）和BRCA1/2突变乳腺癌HRR中的作用。方法：在本研究中，我们使用siRNA在三阴性乳腺癌（TNBC）和BRCA突变乳腺癌细胞系中验证了MAGED1在HRD中的功能。分别用200 μM顺铂（cisplatin）、200 μM奥拉帕利（olaparib）和50 μM尼拉帕利（niraparib）处理Hs578T、HCC-1937（BRCA1 5382insC）和BT-474（BRCA2 c.0391C>A）乳腺癌细胞系后，使用CytoFLEX评估细胞活力。细胞被转染对照siRNA（si-Cont）或两种独立的靶向MAGED1的siRNA（si-MAGED1 #1、si-MAGED1 #2）。结果：使用cytoFLEX流式细胞术，我们研究了siRNA介导的MAGED1抑制，BRCA1/2突变乳腺癌细胞系HCC-1937（BRCA1 5382insC）和BT-474（BRCA2 c.0391C>A）与正常乳腺细胞MCF10A以及乳腺癌细胞系MCF7（管腔A型）和Hs578T（TNBC）相比表现出敏感性增加。此外，发现基于铂的抗癌药顺铂不影响MAGED1抑制，且PARP抑制剂对MAGED1抑制的协同效应在BRCA突变细胞系中更为明显。涉及RNF8、BARD1、RAD51和ATM的进一步研究正在进行中，以进一步阐明HRD和MAGED1的作用。结论：我们的研究表明，沉默MAGED1可增强BRCA1/2突变乳腺癌细胞系对PARP抑制剂的敏感性。这些结果提示MAGED1参与HRD，并可能作为增强乳腺癌PARP抑制剂反应的治疗靶点。

查看英文原文 English abstract

Background: MAGED1 (Melanoma Antigen Gene Family, Member D1) is a member of the MAGE gene family and is known to be involved in various cellular processes such as cell death, cell cycle regulation, and differentiation. Furthermore, previous studies indicate that MAGED1 is essential for double-strand break (DSB) repair via homologous recombination repair (HRR), and reduced MAGED1 expression sensitizes cancer cells to DNA-damaging agents. This study aimed to investigate the role of MAGED1 in HRR in triple-negative breast cancer (TNBC) and BRCA1/2 mutant breast cancer. Methods: In this study, we validated the function of MAGED1 in HRD using siRNA in triple-negative breast cancer (TNBC) and BRCA-mutated breast cancer cell lines. Cell viability was assessed using CytoFLEX after treating Hs578T, HCC-1937 (BRCA1 5382insC), and BT-474 (BRCA2 c.0391C>A) breast cancer cell lines with cisplatin 200 μM, olaparib 200 μM, and niraparib 50 μM, respectively. Cells were transfected with control siRNA (si-Cont) or two independent siRNAs targeting MAGED1 (si-MAGED1 #1, si-MAGED1 #2). Result: Using cytoFLEX flow cytometry, we investigated siRNA-mediated MAGED1 suppression in BRCA1/2 mutant breast cancer cell lines HCC-1937 (BRCA1 5382insC) and BT-474 (BRCA2 c.0391C>A) exhibited increased sensitivity compared to normal breast cells MCF10A and breast cancer cell lines MCF7 (luminal A) and Hs578T (TNBC). Furthermore, the platinum-based anticancer drug cisplatin was found not to affect MAGED1 inhibition, and the synergistic effect of PARP inhibitors on MAGED1 inhibition was more pronounced in BRCA-mutant cell lines. Additional studies involving RNF8, BARD1, RAD51, and ATM are underway to further elucidate the roles of HRD and MAGED1. Conclusions: Our study demonstrates that silencing of MAGED1 enhances sensitivity to PARP inhibitors in BRCA1/2-mutant breast cancer cell lines. These results suggest that MAGED1 is involved in HRD and could be a therapeutic target to enhance PARP inhibitor response in breast cancer.

利益披露 Disclosure

I. Lee, None.. S. Lee, None.. B. Kang, None.. J. Lee, None.. H. Park, None.. J. Moon, None.. J. Park, None.. Y. Chae, None.. E. Kim, None.. S. Jeong, None.. J. Kang, None.

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