Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China.
Central Laboratory of People's Hospital of Ningxia Hui Autonomous Region, Yinchuan, China.
Breast Cancer Res. 2024 Jun 18;26(1):103. doi: 10.1186/s13058-024-01858-x.
Triple-negative breast cancer (TNBC) represents a highly aggressive subset of breast malignancies characterized by its challenging clinical management and unfavorable prognosis. While TFAP2A, a member of the AP-2 transcription factor family, has been implicated in maintaining the basal phenotype of breast cancer, its precise regulatory role in TNBC remains undefined.
In vitro assessments of TNBC cell growth and migratory potential were conducted using MTS, colony formation, and EdU assays. Quantitative PCR was employed to analyze mRNA expression levels, while Western blot was utilized to evaluate protein expression and phosphorylation status of AKT and ERK. The post-transcriptional regulation of TFAP2A by miR-8072 and the transcriptional activation of SNAI1 by TFAP2A were investigated through luciferase reporter assays. A xenograft mouse model was employed to assess the in vivo growth capacity of TNBC cells.
Selective silencing of TFAP2A significantly impeded the proliferation and migration of TNBC cells, with elevated TFAP2A expression observed in breast cancer tissues. Notably, TNBC patients exhibiting heightened TFAP2A levels experienced abbreviated overall survival. Mechanistically, TFAP2A was identified as a transcriptional activator of SNAI1, a crucial regulator of epithelial-mesenchymal transition (EMT) and cellular proliferation, thereby augmenting the oncogenic properties of TFAP2A in TNBC. Moreover, miR-8072 was unveiled as a negative regulator of TFAP2A, exerting potent inhibitory effects on TNBC cell growth and migration. Importantly, the tumor-suppressive actions mediated by the miR-8072/TFAP2A axis were intricately associated with the attenuation of AKT/ERK signaling cascades and the blockade of EMT processes.
Our findings unravel the role and underlying molecular mechanism of TFAP2A in driving tumorigenesis of TNBC. Targeting the TFAP2A/SNAI1 pathway and utilizing miR-8072 as a suppressor represent promising therapeutic strategies for treating TNBC.
三阴性乳腺癌（TNBC）是一种侵袭性很强的乳腺癌亚群，其临床管理具有挑战性，预后不良。虽然 TFAP2A 是 AP-2 转录因子家族的一员，但其在 TNBC 中的精确调节作用仍未确定。
采用 MTS、集落形成和 EdU 检测法评估 TNBC 细胞的生长和迁移能力。采用 qPCR 分析 mRNA 表达水平，采用 Western blot 分析 AKT 和 ERK 的蛋白表达和磷酸化状态。通过荧光素酶报告基因检测法研究了 miR-8072 对 TFAP2A 的转录后调控以及 TFAP2A 对 SNAI1 的转录激活作用。利用异种移植小鼠模型评估 TNBC 细胞的体内生长能力。
选择性沉默 TFAP2A 显著抑制了 TNBC 细胞的增殖和迁移，并且在乳腺癌组织中观察到 TFAP2A 表达升高。值得注意的是，TFAP2A 水平升高的 TNBC 患者总生存期缩短。机制上，TFAP2A 被鉴定为 SNAI1 的转录激活因子，SNAI1 是上皮-间充质转化（EMT）和细胞增殖的关键调节因子，从而增强了 TFAP2A 在 TNBC 中的致癌特性。此外，miR-8072 被揭示为 TFAP2A 的负调控因子，对 TNBC 细胞的生长和迁移具有强大的抑制作用。重要的是，miR-8072/TFAP2A 轴介导的肿瘤抑制作用与 AKT/ERK 信号级联的衰减和 EMT 过程的阻断密切相关。
本研究揭示了 TFAP2A 在驱动 TNBC 肿瘤发生中的作用及其潜在的分子机制。靶向 TFAP2A/SNAI1 通路并利用 miR-8072 作为抑制剂可能是治疗 TNBC 的有前途的治疗策略。
