Department of Biomedical Sciences, J. H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA.
Division of Infectious, Inflammatory and Immunologic Diseases, Department of Internal Medicine, Quillen College of Medicine, ETSU, Johnson City, TN 37614, USA.
Cells. 2021 Dec 29;11(1):97. doi: 10.3390/cells11010097.
Breast cancer, as the most prevalent cancer in women, is responsible for more than 15% of new cancer cases and about 6.9% of all cancer-related death in the US. A major cause of therapeutic failure in breast cancer is the development of resistance to chemotherapy, especially for triple-negative breast cancer (TNBC). Therefore, how to overcome chemoresistance is the major challenge to improve the life expectancy of breast cancer patients. Our studies demonstrate that TNBC cells surviving the chronic treatment of chemotherapeutic drugs show significantly higher expression of the dual serine/threonine and tyrosine protein kinase (DSTYK) than non-treated parental cells. In our in vitro cellular models, DSTYK knockout via the CRISPR/Cas9-mediated technique results in apoptotic cell death of chemoresistant cells upon drug treatment. Moreover, DSTYK knockout promotes chemotherapeutic drug-induced tumor cell death in an orthotopic mouse model. These findings suggest that DSTYK exerts an important and previously unknown role in promoting chemoresistance. Our studies provide fundamental insight into the role of DSTYK in chemoresistance in TNBC cells and lay the foundation for the development of new strategies targeting DSTYK for improving TNBC therapy.
乳腺癌是女性最常见的癌症，占美国新癌症病例的 15%以上，占所有癌症相关死亡的 6.9%以上。乳腺癌治疗失败的一个主要原因是对化疗产生耐药性，特别是三阴性乳腺癌（TNBC）。因此，如何克服化疗耐药性是提高乳腺癌患者预期寿命的主要挑战。我们的研究表明，与未经治疗的亲本细胞相比，经化疗药物慢性处理后存活下来的 TNBC 细胞表现出明显更高水平的双丝氨酸/苏氨酸和酪氨酸蛋白激酶（DSTYK）表达。在我们的体外细胞模型中，通过 CRISPR/Cas9 介导的技术敲除 DSTYK 可导致耐药细胞在药物治疗时发生凋亡性细胞死亡。此外，DSTYK 敲除可促进化疗药物诱导的原位小鼠模型中的肿瘤细胞死亡。这些发现表明 DSTYK 在促进化疗耐药性方面发挥着重要的、以前未知的作用。我们的研究为 DSTYK 在 TNBC 细胞化疗耐药中的作用提供了基本的认识，并为开发针对 DSTYK 的新策略以改善 TNBC 治疗奠定了基础。
