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The 3D Genomic Landscape of Differential Response to EGFR/HER2 Inhibition in Endocrine-Resistant Breast Cancer

ABSTRACT: The 3D Genomic Landscape of Differential Response to EGFR/HER2 Inhibition in Endocrine-Resistant Breast Cancer

PROVIDER: PRJNA603519 | ENA |

REPOSITORIES: ENA

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The 3D Genomic Landscape of Differential Response to EGFR/HER2 Inhibition in Endocrine-Resistant Breast Cancer [HiC]

Project description:Recent studies suggested that crosstalk between ERα and EGFR/HER2 pathways plays a critical role in mediating endocrine therapy resistance. Several targeting EGFR/HER2 signaling inhibitors including FDA-approved lapatinib and gefitinib as well as a novel dual tyrosine kinase inhibitor (TKI) sapitnib showed greater inhibitory efficacies. However, how a 3D chromatin landscape of the response to the inhibition to EGFR/HER2 pathway remains to be elucidated. In this study, we conducted in situ Hi-C and RNA-seq in two ERα+ breast cancer cell systems, tamoxifen-sensitive MCF7 and T47D and tamoxifen-resistant MCF7TR and T47DTR before and after the treatment of sapitnib. We identified differential response of topologically associated domains (TADs), looping genes and expressed genes. Interestingly, we found that many differential TADs and looping genes are reversible, 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. Our data provides a rich resource for further evaluating chromatin structural response to anti-EGFR/HER2 targeted therapies in endocrine-resistant breast cancer.

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Project description:The 3D Genomic Landscape of Differential Response to EGFR/HER2 Inhibition in Endocrine-Resistant Breast Cancer [HiC]

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HOXB7 is an ERÎ± cofactor in the activation of HER2 and multiple ER target genes leading to endocrine resistance

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Project description:Why breast cancers become resistant to tamoxifen despite continued expression of the estrogen receptor alpha (ERα) and what factors are responsible for high HER2 expression in these tumors remains an enigma. HOXB7 ChIP analysis followed by validation showed that HOXB7 physically interacts with ERα, and that the HOXB7-ERα complex enhances transcription of many ERα target genes including HER2. Investigating strategies for controlling HOXB7, our studies revealed that MYC, stabilized via phosphorylation mediated by EGFR-HER2 signaling, inhibits transcription of miRNA-196a, a HOXB7 repressor. This leads to increased expression of HOXB7, ER-target genes and HER2. Repressing MYC using small molecule inhibitors reverses these events, and causes regression of breast cancer xenografts. The MYC-HOXB7-HER2 signaling pathway is eminently targetable in endocrine-resistant breast cancer.

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The 3D Genomic Landscape of Differential Response to EGFR/HER2 Inhibition in Endocrine-Resistant Breast Cancer

Project description:This SuperSeries is composed of the SubSeries listed below.

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HER2 and EGFR dependent activation of RalA in breast cancer

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