Yini Yang1, Lavanya Choppavarapu2, Kun Fang3, Alireza S Naeini4, Bakhtiyor Nosirov2, Jingwei Li5, Ke Yang6, Zhijing He7, Yufan Zhou2, Rachel Schiff8, Rong Li9, Yanfen Hu10, Junbai Wang11, Victor X Jin12. 1. Minimally Invasive Surgical Center, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China; Department of Molecular Medicine, University of Texas Health San Antonio, TX 78229, USA. 2. Department of Molecular Medicine, University of Texas Health San Antonio, TX 78229, USA. 3. Program of Biomedical Engineering, UTHSA-UTSA Joint Graduate Program, San Antonio, TX 78229, USA. 4. Department of Pathology, Oslo University Hospital - Norwegian Radium Hospital, Montebello, 0310 Oslo, Norway; Department of Microbiology, Oslo University Hospital - Norwegian Radium Hospital, Montebello, 0310 Oslo, Norway. 5. Department of Molecular Medicine, University of Texas Health San Antonio, TX 78229, USA; Department of Gastrointestinal Surgery, Third Xiangya Hospital, Central South University, Changsha, Hunan 410006, China. 6. Department of Molecular Medicine, University of Texas Health San Antonio, TX 78229, USA; Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China. 7. Department of Molecular Medicine, University of Texas Health San Antonio, TX 78229, USA; Department of Stomatology, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China. 8. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA; Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA; Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA. 9. Department of Biochemistry & Molecular Medicine, The George Washington University, Washington, DC 20037, USA. 10. Department of Anatomy & Cell Biology, The George Washington University, Washington, DC 20037, USA. 11. Department of Pathology, Oslo University Hospital - Norwegian Radium Hospital, Montebello, 0310 Oslo, Norway. Electronic address: Junbai.wang@rr-research.no. 12. Department of Molecular Medicine, University of Texas Health San Antonio, TX 78229, USA. Electronic address: jinv@uthscsa.edu.
Abstract
BACKGROUND: Recent studies suggested that crosstalk between ERα and EGFR/HER2 pathways plays a critical role in mediating endocrine therapy resistance. Several inhibitors targeting EGFR/HER2 signaling, including FDA-approved lapatinib and gefitinib as well as a novel dual tyrosine kinase inhibitor (TKI) sapitinib, showed greater therapeutic efficacies. However, how 3D chromatin landscape responds to the inhibition of EGFR/HER2 pathway remains to be elucidated. METHODS: In this study, we conducted in situ Hi-C and RNA-seq in two ERα+ breast cancer cell systems, 1) parental MCF7 cells and its associated tamoxifen-resistant MCF7TR cells; and 2) parental T47D cells and its associated tamoxifen-resistant T47DTR cells, before and after the treatment of sapitinib. RESULTS: We identified differential responses in topologically associated domains (TADs), looping genes and expressed genes. Interestingly, we found that many differential TADs and looping genes are reversible after sapitinib treatment, indicating that EGFR/HER2 signaling may play a role in reshaping and rewiring the high order genome organization. We further examined and recapitulated the reversible looping genes in 3D spheroids of breast cancer cells, demonstrating that 3D cell culture spheroid of breast cancer cells could be a potential preclinical breast cancer model for studying 3D chromatin regulation. CONCLUSIONS: Our study has provided significant insights into our understanding of 3D genomic landscape changes in response to EGFR/HER2 Inhibition in endocrine-resistant breast cancer cells. Our data provides a rich resource for further evaluating chromatin structural responses to EGFR/HER2 targeted therapies in endocrine-resistant breast cancer cells. Our analyses suggest that these alterations of chromatin structures and transcriptional programs may provide new avenues for intervention or designing of patient selection for targeted endocrine treatment.
BACKGROUND: Recent studies suggested that crosstalk between ERα and EGFR/HER2 pathways plays a critical role in mediating endocrine therapy resistance. Several inhibitors targeting EGFR/HER2 signaling, including FDA-approved lapatinib and gefitinib as well as a novel dual tyrosine kinase inhibitor (TKI) sapitinib, showed greater therapeutic efficacies. However, how 3D chromatin landscape responds to the inhibition of EGFR/HER2 pathway remains to be elucidated. METHODS: In this study, we conducted in situ Hi-C and RNA-seq in two ERα+ breast cancer cell systems, 1) parental MCF7 cells and its associated tamoxifen-resistant MCF7TR cells; and 2) parental T47D cells and its associated tamoxifen-resistant T47DTR cells, before and after the treatment of sapitinib. RESULTS: We identified differential responses in topologically associated domains (TADs), looping genes and expressed genes. Interestingly, we found that many differential TADs and looping genes are reversible after sapitinib treatment, indicating that EGFR/HER2 signaling may play a role in reshaping and rewiring the high order genome organization. We further examined and recapitulated the reversible looping genes in 3D spheroids of breast cancer cells, demonstrating that 3D cell culture spheroid of breast cancer cells could be a potential preclinical breast cancer model for studying 3D chromatin regulation. CONCLUSIONS: Our study has provided significant insights into our understanding of 3D genomic landscape changes in response to EGFR/HER2 Inhibition in endocrine-resistant breast cancer cells. Our data provides a rich resource for further evaluating chromatin structural responses to EGFR/HER2 targeted therapies in endocrine-resistant breast cancer cells. Our analyses suggest that these alterations of chromatin structures and transcriptional programs may provide new avenues for intervention or designing of patient selection for targeted endocrine treatment.
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