Dr. Weeks’ Comment: This immunotherapy (oncoimmunology) is more promising that the standard of care: chemo and radiation.
Targeted Toxin Gene Therapy Of Breast Cancer Stem Cells Using CXCR1 Promoter And bFGF 5′UTR
Published 25 October 2019 Volume 2019:12
Department of Medical Biotechnology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
Background: Breast cancer stem cells (BCSCs) are cells with a higher ability to metastasis and resistance to conventional treatments. They have a phenotype of (CD44high/CD24low) and the unlimited ability for proliferation. Development of strategies to target the BCSC population may lead to the establishment of more effective cancer therapies. Pseudomonas exotoxin A (PE) is a potent cytotoxic protein. CXCR1 promoter provides BCSC and HER2 specificity on transcription level. 5′UTR of the basic fibroblast growth factor-2 (bFGF 5ʹUTR) provides tumor specificity on translation level. Here, we utilized a mutant form of PE encoding DNA “PE38”, CXCR1 promoter and bFGF 5ʹUTR to target BCSCs.
Results: The percentage of CD44high/CD24low population did not correlate to mammosphere forming efficiency (MFE). Given that the percentage of CD44 high/CD24 low is not a conclusive BCSC profile, we based our work on the mammosphere assay. However, in comparison with MCF10A, the two tumorigenic cell lines had higher MFE, probably due to their higher BCSC content. Reporter assay and real-time PCR results demonstrated that CXCR1 promoter combined with bFGF 5ʹUTR increased BCSC-specific gene expression. Meanwhile, tightly regulated expression of PE38 using these two gene regulatory elements resulted in high levels of cell death in the two tumorigenic cell lines while having little toxicity toward normal MCF10A.
Conclusion: Our data show that PE38, CXCR1 promoter and bFGF 5ʹUTR in combination can be considered as a promising tool for killer gene therapy of breast cancer.