BET-directed PROTACs in triple negative breast cancer cell lines MDA-MB-231 and MDA-MB-436.

IF 3 3区医学 Q2 ONCOLOGY Breast Cancer Research and Treatment Pub Date : 2024-11-01 Epub Date: 2024-06-19 DOI:10.1007/s10549-024-07403-w

Maryana Teufelsbauer, Sandra Stickler, Marie-Therese Eggerstorfer, Dennis Clyde Hammond, Gerhard Hamilton

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Abstract

Purpose: This study aims to find whether the proliferation and migration of triple negative breast cancer (TNBC) cell lines can be reduced by treatment with bromodomain and extra-terminal domain (BET) inhibitor JQ1 and BET protein targeting chimeras (PROTACs) ARV-771 and MZ1.

Methods: Cytotoxicity tests, scratch migration assays and western blot proteome profiler arrays for protein expression of cancer-related proteins were used to evaluate the impact of a BET-inhibitor and two BET-directed PROTACs on cell viability, migration and on protein expression.

Results: JQ1 and the PROTACs MZ1 and ARV-771 significantly inhibited the growth and migration of the KRAS G13D-mutated MDA-MB-231 cells. In this cell line, the PROTACs suppressed the residual expression of ERBB2/HER2, 3 and 4 that are essential for the proliferation of breast cancer cells and this cell line proved sensitive to HER2 inhibitors. In contrast, the effects of the PROTACs on the protein expression of MDA-MB-436 cells mostly affected cytokines and their cognate receptors.

Conclusion: The degradation of BET-protein by PROTACs demonstrated significant anti-proliferative effects. The KRAS-mutated MDA-MB-231 cells belong to the low-HER2 expressing tumors that have a poorer prognosis compared to HER2-null patients. Since first oral PROTACs against tumor hormone receptors are in clinical trials, this mode of tumor therapy is expected to become an important therapeutic strategy in the future treatment of TNBC.

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三阴性乳腺癌细胞系 MDA-MB-231 和 MDA-MB-436 中的 BET 定向 PROTACs。

目的：本研究旨在探讨溴基底域和末端外域（BET）抑制剂JQ1和BET蛋白靶向嵌合体（PROTACs）ARV-771和MZ1是否能减少三阴性乳腺癌（TNBC）细胞系的增殖和迁移：方法：采用细胞毒性试验、划痕迁移试验和Western印迹蛋白质组图谱阵列检测癌症相关蛋白质的表达，评估一种BET抑制剂和两种BET靶向PROTACs对细胞活力、迁移和蛋白质表达的影响：结果：JQ1以及PROTACs MZ1和ARV-771显著抑制了KRAS G13D突变的MDA-MB-231细胞的生长和迁移。在该细胞系中，PROTACs抑制了乳腺癌细胞增殖所必需的ERBB2/HER2、3和4的残余表达，证明该细胞系对HER2抑制剂敏感。相比之下，PROTACs 对 MDA-MB-436 细胞蛋白表达的影响主要涉及细胞因子及其同源受体：结论：PROTACs 对 BET 蛋白的降解具有显著的抗增殖作用。KRAS突变的MDA-MB-231细胞属于低HER2表达肿瘤，与HER2缺失患者相比预后较差。由于首个针对肿瘤激素受体的口服 PROTACs 已进入临床试验阶段，这种肿瘤治疗模式有望成为未来治疗 TNBC 的重要治疗策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Breast Cancer Research and Treatment 医学-肿瘤学

CiteScore

6.80

自引率

2.60%

发文量

342

审稿时长

1 months

期刊介绍： Breast Cancer Research and Treatment provides the surgeon, radiotherapist, medical oncologist, endocrinologist, epidemiologist, immunologist or cell biologist investigating problems in breast cancer a single forum for communication. The journal creates a "market place" for breast cancer topics which cuts across all the usual lines of disciplines, providing a site for presenting pertinent investigations, and for discussing critical questions relevant to the entire field. It seeks to develop a new focus and new perspectives for all those concerned with breast cancer.