SOX4-mediated FBW7 transcriptional upregulation confers Tamoxifen resistance in ER+ breast cancers via GATA3 downregulation
| Autor: | Akshay Sharma, Gatha Thacker, Mukul Mishra, Anil Kumar Singh, Vishal Upadhyay, Sabyasachi Sanyal, Arun Kumar Trivedi |
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| Rok vydání: | 2022 |
| Předmět: |
History
Polymers and Plastics Antineoplastic Agents Hormonal Down-Regulation Breast Neoplasms GATA3 Transcription Factor General Medicine Industrial and Manufacturing Engineering General Biochemistry Genetics and Molecular Biology SOXC Transcription Factors Up-Regulation Gene Expression Regulation Neoplastic Tamoxifen Drug Resistance Neoplasm Cell Line Tumor MCF-7 Cells Humans Female RNA Messenger Business and International Management General Pharmacology Toxicology and Pharmaceutics Cell Proliferation |
| Zdroj: | Life Sciences. 303:120682 |
| ISSN: | 0024-3205 |
| Popis: | Tamoxifen-mediated endocrine therapy has been standard treatment for ER+ breast cancers; however, majority of them acquire resistance leading to disease relapse. Although numerous substrates of E3 ligase FBW7 are known, only a handful of factors that regulate FBW7 expression and function are reported. In particular, there remains a lack of in-depth understanding of FBW7 transcriptional regulation.Luciferase reporter assay was performed after cloning full length and truncated FBW7 promoters followed by Chromatin immunoprecipitation assay to validate binding of SOX4 on FBW7 promoter. Transcriptional regulation of FBW7 by SOX4 and their biological consequences with respect to ER+ breast cancer was then evaluated using immunoblotting and other cell based assays.SOX4 positively regulates FBW7 at transcriptional level by binding to three putative SOX4 biding sites within 3.1 kb long FBW7 promoter. Analysis of publicly available RNAseq datasets also showed a positive correlation between SOX4 and FBW7 mRNA in cancer cell lines and patient samples. qPCR and Immunoblotting confirmed that transiently or stably expressed SOX4 induced both endogenous FBW7 mRNA and protein levels. Our findings further demonstrated that increased levels of SOX4 and FBW7 in MCF7 mammospheres promoted cancer stemness and tumor cell dormancy. We further showed that both MCF7 mammospheres and MCFTargeting SOX4-FBW7-GATA3 axis may overcome tamoxifen resistance in ER+ breast cancers. |
| Databáze: | OpenAIRE |
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