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Genome wide analysis of transcripts regulated by PAX2 and Tamoxifen in MCF-7 cells

ABSTRACT: The aim of the study is to understand the role of the transcription factor PAX2 in estrogen receptor positive breast cancer cell line by using GRO-seq. MCF-7-PAX2 stable cells were cultured in full media and treated with doxycycline (50ng/ml) for 16 hours to induce overexpression of PAX2. Then cells were treated with 4-OH-tamoxifen (1μM) for 6 hours. All 4 treatments (Veh, Tam, Dox, DoxTam) were performed in duplicates. After treatments, nuclei were isolated and used for nuclear run-on and subsequent GRO-seq library preparation. Libraries were sequenced and data analysis showed that PAX2 could repress estrogen target genes and induce genes enriched in cytokine (TNF-alpha and INF-gamma) related pathways. When combined with tamoxifen, PAX2 could further repress estrogen target genes to a higher degree, and induce genes enriched in p53 related pathway. Moreover, PAX2 could induce the transcription of some intergenic transcripts (potential enhancers) to activate the transcription of nearby genes with could predict good outcome in estrogen receptor positive breast cancer. Overall our finding suggests that PAX2 could benifit ER positive breast cancer by 1) repressing estrogen target genes, and this effect is enhanced by tamoxifen 2) activating cell death/growth arrest related pathways, which is enhanced by potential enhancer transcription induced by PAX2 itself.

ORGANISM(S): Homo sapiens

PROVIDER: GSE139928 | GEO | 2019/11/06

REPOSITORIES: GEO

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Chromatin immunoprecipitation of estrogen receptor in human breast cancer cells (MCF-7) treated with estrogen

Project description:Cross talk between the Estrogen Receptor (ER) and ErbB2/HER-2 pathways have long been implicated in breast cancer aetiology and drug response1, yet no direct connection at a transcriptional level has been shown. We now show that estrogen-ER and tamoxifen-ER complexes directly repress ErbB2 transcription via a cis-regulatory element within the ERBB2 gene. We implicate the Paired Box 2 gene product (Pax2), in a novel role, as a crucial mediator of ER repression of ErbB2 by the anti-cancer drug tamoxifen. We show that Pax2 and the ER co-activator AIB-1/SRC-3 compete for binding and regulation of ErbB2 transcription, the outcome of which determines tamoxifen response in breast cancer cells. The repression of ErbB2 by ER-Pax2 links these two important breast cancer subtypes and suggests that aggressive ErbB2 positive tumours can originate from ER positive luminal tumours by circumventing this repressive mechanism. These data provide mechanistic insight into the molecular basis of endocrine resistance in breast cancer.

2008-09-27 | E-TABM-563 | biostudies-arrayexpress

Genome wide analysis of PAX2 chromatin interaction in MCF-7 cell

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Gene expression profiling of invasive breast cancer events from the tamoxifen prevention trial

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2011-12-08 | E-GEOD-12665 | biostudies-arrayexpress

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Transcription profiling of endometrial epithelial cells (EECs) to understand actions of tamoxifen in the uterus and its molecular effectors in endometrial carcinogenesis

2007-09-08 | E-GEOD-3013 | biostudies-arrayexpress

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2006-07-28 | GSE4025 | GEO

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Transcription profiling of human MCF-7 breast cancer cell line transfected with adenovirus expressing Erbeta treated with estrogen or tamoxifen reveals tamoxifen can selectively regulate a unique set of >60 genes, which are minimally regulated by estradiol (E2) or raloxifene.

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