Ncube Stephanie M, Nagarajan ArulJothi, Lang Dirk, Sinkala Musalula, Burmeister Carly A, Serala Karabo, Blackburn Jonathan, Prince Sharon
Division of Cell Biology, Department of Human Biology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
Department of Genetic Engineering, College of Engineering and Technology, SRM Institute of Science and Technology, Kattankulathur, India.
Mol Cancer Res. 2025 Jan 2;23(1):20-32. doi: 10.1158/1541-7786.MCR-23-1031.
Breast cancer is the second leading cause of death in women globally, and it remains a health burden due to poor therapy response, cancer cell drug resistance, and the debilitating side effects associated with most therapies. One approach to addressing the need to improve breast cancer therapies has been to elucidate the mechanism(s) underpinning this disease to identify key drivers that can be targeted in molecular therapies. The T-box transcription factor, TBX3, is upregulated in breast cancer, in which it contributes to important oncogenic processes, and it has been validated as a potential therapeutic target. Here, we investigated the molecular mechanisms that upregulate TBX3 in breast cancer, and we show that it involves transcriptional activation by c-Myc, post-translational modification by AKT1 and AKT3, and interaction with the molecular chaperone Hsc70. Together, the results from this study provide evidence that c-Myc, AKT, Hsc70, and TBX3 form part of an important oncogenic pathway in breast cancer and thus reveal versatile ways of interfering with the oncogenic activity of TBX3 for the treatment of this neoplasm. Implications: Targeting the c-Myc/AKT/TBX3/Hsc70 signaling axis may be an effective treatment strategy for TBX3-driven breast cancer.
乳腺癌是全球女性第二大死因，由于治疗反应不佳、癌细胞耐药性以及大多数治疗方法带来的使人虚弱的副作用，它仍然是一个健康负担。满足改善乳腺癌治疗需求的一种方法是阐明该疾病的潜在机制，以确定可在分子治疗中作为靶点的关键驱动因素。T盒转录因子TBX3在乳腺癌中上调，它在乳腺癌中促成重要的致癌过程，并且已被确认为一个潜在的治疗靶点。在此，我们研究了乳腺癌中上调TBX3的分子机制，结果表明这涉及c-Myc的转录激活、AKT1和AKT3的翻译后修饰以及与分子伴侣Hsc70的相互作用。总之，本研究结果证明c-Myc、AKT、Hsc70和TBX3构成了乳腺癌中一条重要致癌途径的一部分，从而揭示了多种干扰TBX3致癌活性以治疗该肿瘤的方法。启示：靶向c-Myc/AKT/TBX3/Hsc70信号轴可能是治疗TBX3驱动型乳腺癌的有效策略。
