Aim: Metastasis to the brain has become a major limitation to the life expectancy and quality of life for many patients with breast cancer. Unfortunately, other than radiation and palliative treatments with trastuzuma...Aim: Metastasis to the brain has become a major limitation to the life expectancy and quality of life for many patients with breast cancer. Unfortunately, other than radiation and palliative treatments with trastuzumab, and pertuzumab, no effective therapy for brain metastases is currently available. This study seeks to identify novel gene targets and pharmaceutical Intervention against breast cancer brain metastasis. Methods: The detailed methods applied to this study, including comparative RNA sequencing and bioinformatics analysis of sequence data, ingenuity pathway analysis, protein-protein interaction analysis, high throughput screening of clinical and pre-clinical drugs, cell viability and proliferation assay, toxicity and apoptosis assay using fluorescence-activated cell sorting, real-time PCR, western blotting, statistical analysis of data. Results: The study reveals critical roles for SRC, ERBB2, PIK3CA, and GABA in the proliferation and survival of breast cancer brain metastatic (BBM) cells and showed that SRC- and ERBB2-mediated activation of PIK3-AKT/mTOR signaling regulates BBM cell survival. Selective inhibition of these candidate genes alone or in combination induces robust apoptosis in BBM cells Conclusion: The findings of this study provide a rationale for further preclinical evaluation of SRC-targeting regimens in combination with ERBB2 inhibitors and/or GABA agonists to target breast cancer brain metastasis.展开更多
基金Department of Defense Breast Cancer Research Program(BC142323)the Margaret E.Early Medical Research Trust for experiment design,collection,analysis,and interpretation of data,and writing of the manuscript
文摘Aim: Metastasis to the brain has become a major limitation to the life expectancy and quality of life for many patients with breast cancer. Unfortunately, other than radiation and palliative treatments with trastuzumab, and pertuzumab, no effective therapy for brain metastases is currently available. This study seeks to identify novel gene targets and pharmaceutical Intervention against breast cancer brain metastasis. Methods: The detailed methods applied to this study, including comparative RNA sequencing and bioinformatics analysis of sequence data, ingenuity pathway analysis, protein-protein interaction analysis, high throughput screening of clinical and pre-clinical drugs, cell viability and proliferation assay, toxicity and apoptosis assay using fluorescence-activated cell sorting, real-time PCR, western blotting, statistical analysis of data. Results: The study reveals critical roles for SRC, ERBB2, PIK3CA, and GABA in the proliferation and survival of breast cancer brain metastatic (BBM) cells and showed that SRC- and ERBB2-mediated activation of PIK3-AKT/mTOR signaling regulates BBM cell survival. Selective inhibition of these candidate genes alone or in combination induces robust apoptosis in BBM cells Conclusion: The findings of this study provide a rationale for further preclinical evaluation of SRC-targeting regimens in combination with ERBB2 inhibitors and/or GABA agonists to target breast cancer brain metastasis.
