Triple-negative breast cancer (TNBC) stands out as the most aggressive subtype within the spectrum of breast cancer. The current clinical guidelines propose treatment strategies involving cytotoxic agents like epirubicin or paclitaxel. However, the emergence of acquired resistance frequently precipitates secondary tumor recurrence or the spread of metastasis. In recent times, significant attention has been directed toward the transcription factor RUNX2, due to its pivotal role in both tumorigenesis and the progression of cancer. Previous researches suggest that RUNX2 might be intricately linked to the development of resistance against chemotherapy, with its mechanism of action possibly intertwined with the signaling of TGF-β. Nevertheless, the precise interplay between their effects and the exact molecular mechanisms underpinning chemoresistance in TNBC remain elusive. Therefore, we have taken a multifaceted approach from in vitro and in vivo experiments to validate the relationship between RUNX2 and TGF-β and to search for their pathogenic mechanisms in chemoresistance. In conclusion, we found that RUNX2 affects chemoresistance by regulating cancer cell stemness through direct binding to TGF-β, and that TGF-β dually regulates RUNX2 expression. The important finding will provide a new reference for clinical reversal of the development of chemoresistance in breast cancer.

三阴性乳腺癌 (TNBC) 是乳腺癌谱系中最具侵袭性的亚型。目前的临床指南提出了涉及表柔比星或紫杉醇等细胞毒性药物的治疗策略。然而，获得性耐药的出现常常会导致继发性肿瘤复发或转移扩散。近年来，转录因子 RUNX2 由于其在肿瘤发生和癌症进展中的关键作用而受到极大关注。先前的研究表明，RUNX2 可能与化疗耐药的发展有着复杂的联系，其作用机制可能与 TGF-β 信号传导交织在一起。然而，它们的作用与 TNBC 化疗耐药性的确切分子机制之间的精确相互作用仍然难以捉摸。因此，我们采取多方面的体外和体内实验来验证RUNX2和TGF-β之间的关系，并寻找其化疗耐药的致病机制。总之，我们发现RUNX2通过直接与TGF-β结合调节癌细胞干性来影响化疗耐药性，并且TGF-β双重调节RUNX2表达。这一重要发现将为临床逆转乳腺癌化疗耐药的发展提供新的参考。