TY - JOUR
T1 - The 3D genomic landscape of differential response to EGFR/HER2 inhibition in endocrine-resistant breast cancer cells
AU - Yang, Yini
AU - Choppavarapu, Lavanya
AU - Fang, Kun
AU - Naeini, Alireza S.
AU - Nosirov, Bakhtiyor
AU - Li, Jingwei
AU - Yang, Ke
AU - He, Zhijing
AU - Zhou, Yufan
AU - Schiff, Rachel
AU - Li, Rong
AU - Hu, Yanfen
AU - Wang, Junbai
AU - Jin, Victor X.
N1 - Funding Information:
Rachel Schiff reported research funding from AstraZeneca, GlaxoSmithKline, Gilead Sciences, and PUMA Biotechnology, and is a consulting/advisory committee member for Macrogenics and Eli Lilly outside the submitted work. The remaining authors declare no competing interests.
Funding Information:
This project was partially supported by grants from NIH R01GM114142 (VXJ), U54CA217297 (VXJ), R01CA220578 (RL, YH) and CPRIT RP170126 (VXJ, YH, RL), P50CA186784 (SPORE) (R.S.), Breast Cancer Research Foundation (BCRF) 16-142 , 17-143 , 18-145 (R.S.). JW is supported by South-Eastern Norway Regional Health Authority ( HSØ 2017061 and HSØ 2018107 ), and the usage of high performance computer resource is supported by the Norwegian Research Council NOTUR project ( nn4605k ).
Publisher Copyright:
© 2020 The Author(s)
PY - 2020/11
Y1 - 2020/11
N2 - 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.
AB - 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.
KW - Altered domains
KW - EGFR/HER2 inhibitor
KW - Reversible gene looping
KW - Tamoxifen resistant breast cancer
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U2 - 10.1016/j.bbagrm.2020.194631
DO - 10.1016/j.bbagrm.2020.194631
M3 - Article
C2 - 32956836
AN - SCOPUS:85091761490
VL - 1863
JO - Biochimica et Biophysica Acta - Gene Regulatory Mechanisms
JF - Biochimica et Biophysica Acta - Gene Regulatory Mechanisms
SN - 1874-9399
IS - 11
M1 - 194631
ER -