2019
DOI: 10.1101/767871
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Coordinate Enhancer Reprogramming by GATA3 and AP1 Promotes Phenotypic Plasticity to Achieve Breast Cancer Endocrine Resistance

Abstract: Acquired therapy resistance is a major problem for anticancer treatment, yet the underlying molecular mechanisms remain unclear. Using an established breast cancer cellular model for endocrine resistance, we show that hormone resistance is associated with enhanced phenotypic plasticity, indicated by a general downregulation of luminal/epithelial differentiation markers and upregulation of basal/mesenchymal invasive markers. Our extensive omics studies, including GRO-seq on enhancer landscapes, demonstrate that… Show more

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Cited by 4 publications
(6 citation statements)
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“…Our findings were in large agreement to previously known work on the role of FOXA1 and GATA3 in the literature in regulation, maintenance and oncogenic programs of luminal bladder cancers [8,[19][20][21]. Interestingly, we found a novel co-regulation of FOXA1 and GATA3 with a common binding partner of AP-1 complex like breast cancers [55,56] and drive distal-enhancers, but not promoters. Our comprehensive 3D genome map shows distinct chromatin contact interaction networks available to luminal and basal BLCA.…”
Section: Discussionsupporting
confidence: 92%
“…Our findings were in large agreement to previously known work on the role of FOXA1 and GATA3 in the literature in regulation, maintenance and oncogenic programs of luminal bladder cancers [8,[19][20][21]. Interestingly, we found a novel co-regulation of FOXA1 and GATA3 with a common binding partner of AP-1 complex like breast cancers [55,56] and drive distal-enhancers, but not promoters. Our comprehensive 3D genome map shows distinct chromatin contact interaction networks available to luminal and basal BLCA.…”
Section: Discussionsupporting
confidence: 92%
“…However, there are many ways for tumours to acquire resistance, and recently it has been shown that changes to the regulatory chromatin landscape can permit resistance in several scenarios, including endocrine resistance in breast cancer (Bi et al, 2020), BET inhibitor resistance in acute myeloid leukaemia (Bell et al, 2019), and PDGFRA inhibitor resistance in glioblastoma (Liau et al, 2017). Here we have focussed on RTK pathways driven by ERBB2 amplifications in OAC and demonstrate that widespread rewiring of the regulatory chromatin landscape is a major driver towards acquiring drug resistance.…”
Section: Discussionmentioning
confidence: 91%
“…Drug resistance in OAC often arises due to the selection of cells containing compensatory mutations (Kim et al, 2014;Janjigian et al, 2018;Wang et al, 2019). However, it is becoming increasingly recognised that changes to the epigenetic landscape can also play an important role in drug resistance, particularly in enabling the survival of "persistor" cells, which ultimately gather additional mutations to adopt a stable resistant form (Bi et al, 2020;Sharma et al, 2010;Ramirez et al, 2016;reviewed in Hammerlindl and Schaider, 2018;Shen et al, 2020).…”
Section: Introductionmentioning
confidence: 99%
“…MEME ChIP TFB motif enrichment at rescued enhancers shows the presence of several transcription master regulators. The most frequent enriched motif is GATA3 (20/48 TFs), which has been recently described as a key factor in enhancer-dependent cell reprogramming [ 12 ] and T-cell differentiation [ 13 ]. The second most frequent motif (19/48 TFs) is SP1, known for binding enhancers, regulating chromatin looping [ 57 ] and playing a key role in malignant hematopoiesis, through its interaction with GATA1 [ 11 ].…”
Section: Resultsmentioning
confidence: 99%