Talukdar Priyanka Dey, Roy Himansu, Chatterji Urmi
Cancer Research Laboratory, Department of Zoology, University of Calcutta, 35 Ballygunge Circular Road, Kolkata, West Bengal, 700019, India.
Department of Surgery, Medical College, Kolkata, 700073, India.
Mol Biol Rep. 2025 Jan 24;52(1):154. doi: 10.1007/s11033-025-10264-1.
Current treatment strategies for hormone-dependent breast cancers, including adjuvant endocrine therapy, often fail due to persistence of breast cancer stem cells (brCSCs), which are significant contributors to tumor recurrence and treatment resistance. Therefore, gaining deeper insights into the molecular regulators driving breast cancer aggressiveness is important. Moreover, given the complexities and expenses involved in developing new pharmacological agents, the strategic repurposing of existing FDA-approved drugs to target these key molecular pathways presents a compelling approach for identifying novel therapeutic interventions aimed at mitigating tumor refractoriness.
The study employs survival analysis from TCGA database, protein expression analyses alongside aldefluor assays, sphere formation efficiency tests to evaluate cellular stemness, and DCFDA analysis combined with antioxidant enzyme assays to investigate redox imbalance in brCSCs. These analyses were conducted following the genetic deletion of YAP/TAZ and pharmacological treatment with verteporfin.
The study demonstrated that transcriptional co-activators YAP/TAZ are significantly upregulated in chemotreated ER patient breast tumors and MCF-7 mammospheres, where it was found to interact with the transcription factor SOX2 within the nuclear compartment. Genetic ablation and pharmacological inhibition of YAP/TAZ markedly impaired stemness properties and disrupted redox homeostasis in the mammospheres. Additionally, treatment with verteporfin led to a substantial reduction in the frequency and viability of brCSCs, suggesting their effective eradication.
This study highlights the potential of repurposing verteporfin, an FDA-approved drug originally formulated for age-related macular degeneration, as a therapeutic agent for targeting YAP/TAZ-mediated stemness and redox balance in brCSCs, thereby reducing their viability in ER-positive breast cancers.
激素依赖性乳腺癌的当前治疗策略，包括辅助内分泌治疗，常常因乳腺癌干细胞（brCSCs）的持续存在而失败，这些干细胞是肿瘤复发和治疗抵抗的重要因素。因此，深入了解驱动乳腺癌侵袭性的分子调节因子很重要。此外，鉴于开发新的药理学药物涉及的复杂性和费用，将现有的FDA批准药物重新用于靶向这些关键分子途径，为确定旨在减轻肿瘤难治性的新型治疗干预措施提供了一种有吸引力的方法。
该研究采用来自TCGA数据库的生存分析、蛋白质表达分析以及醛荧光测定、球体形成效率测试以评估细胞干性，以及DCFDA分析结合抗氧化酶测定来研究brCSCs中的氧化还原失衡。这些分析是在YAP/TAZ基因缺失和用维替泊芬进行药物治疗后进行的。
该研究表明，转录共激活因子YAP/TAZ在化疗后的雌激素受体（ER）阳性患者乳腺肿瘤和MCF-7乳腺球中显著上调，发现其在核内与转录因子SOX2相互作用。YAP/TAZ的基因消融和药物抑制显著损害了乳腺球中的干性特性并破坏了氧化还原稳态。此外，用维替泊芬治疗导致brCSCs的频率和活力大幅降低，表明它们被有效根除。
本研究强调了将维替泊芬（一种最初用于治疗年龄相关性黄斑变性的FDA批准药物）重新用作治疗剂以靶向brCSCs中YAP/TAZ介导的干性和氧化还原平衡的潜力，从而降低其在ER阳性乳腺癌中的活力。
