三阴性乳腺癌（TNBC）的特点是侵袭性生长以及高复发和转移倾向。 TNBC 中 c-MET 和 EGFR 同时过度表达与更差的临床病理特征和不良结果相关。尽管新型 c-MET 抑制剂的开发和第三代 EGFR 抑制剂的出现代表了有前景的治疗选择，但高昂的成本限制了这些药物的可及性。在本研究中，我们旨在探讨良性前列腺增生仿制药多沙唑嗪（DOXA）针对TNBC的治疗潜力。从细胞活力、凋亡、细胞活力等方面评估了DOXA对体外TNBC细胞系的影响。 c-MET/EGFR 信号通路、分子对接研究以及对癌症干细胞 (CSC) 样特性的影响。采用 CSC 体内转移模型来评估 DOXA 的功效。DOXA 通过 caspase 激活诱导细胞凋亡，对 TNBC 细胞表现出显着的抗增殖作用。分子对接研究揭示了 DOXA 与 c-MET 和 EGFR 的酪氨酸激酶结构域的直接相互作用。因此，DOXA 破坏了重要的生存途径，包括 AKT、MEK/ERK 和 JAK/STAT3，同时抑制 CSC 样特征，包括 CD44high/CD24low 亚群、乙醛脱氢酶 1 (ALDH1) 活性和微球的形成。在富含 CSC 群体的原位同种异体移植模型中，发现 DOXA 给药可抑制肿瘤生长、肿瘤内和肿瘤周围血管生成以及远处转移。此外，没有观察到 DOXA 对肝或肾功能的毒性作用。我们的研究结果强调了 DOXA 作为转移性 TNBC 治疗选择的潜力，值得进一步研究。© 2023。作者。

Triple-negative breast cancer (TNBC) is characterized by aggressive growth and a high propensity for recurrence and metastasis. Simultaneous overexpression of c-MET and EGFR in TNBC is associated with worse clinicopathological features and unfavorable outcomes. Although the development of new c-MET inhibitors and the emergence of 3rd-generation EGFR inhibitors represent promising treatment options, the high costs involved limit the accessibility of these drugs. In the present study, we sought to investigate the therapeutic potential of doxazosin (DOXA), a generic drug for benign prostate hyperplasia, in targeting TNBC.The effect of DOXA on TNBC cell lines in vitro was evaluated in terms of cell viability, apoptosis, c-MET/EGFR signaling pathway, molecular docking studies and impact on cancer stem cell (CSC)-like properties. An in vivo metastatic model with CSCs was used to evaluate the efficacy of DOXA.DOXA exhibits notable anti-proliferative effects on TNBC cells by inducing apoptosis via caspase activation. Molecular docking studies revealed the direct interaction of DOXA with the tyrosine kinase domains of c-MET and EGFR. Consequently, DOXA disrupts important survival pathways including AKT, MEK/ERK, and JAK/STAT3, while suppressing CSC-like characteristics including CD44high/CD24low subpopulations, aldehyde dehydrogenase 1 (ALDH1) activity and formation of mammospheres. DOXA administration was found to suppress tumor growth, intra- and peri-tumoral angiogenesis and distant metastasis in an orthotopic allograft model with CSC-enriched populations. Furthermore, no toxic effects of DOXA were observed in hepatic or renal function.Our findings highlight the potential of DOXA as a therapeutic option for metastatic TNBC, warranting further investigation.© 2023. The Author(s).