Dataset Information

FOXA1, GATA3 and PPAR? Cooperate to Drive Luminal Subtype in Bladder Cancer: A Molecular Analysis of Established Human Cell Lines.

ABSTRACT: Discrete bladder cancer molecular subtypes exhibit differential clinical aggressiveness and therapeutic response, which may have significant implications for identifying novel treatments for this common malignancy. However, research is hindered by the lack of suitable models to study each subtype. To address this limitation, we classified bladder cancer cell lines into molecular subtypes using publically available data in the Cancer Cell Line Encyclopedia (CCLE), guided by genomic characterization of bladder cancer by The Cancer Genome Atlas (TCGA). This identified a panel of bladder cancer cell lines which exhibit genetic alterations and gene expression patterns consistent with luminal and basal molecular subtypes of human disease. A subset of bladder cancer cell lines exhibit in vivo histomorphologic patterns consistent with luminal and basal subtypes, including papillary architecture and squamous differentiation. Using the molecular subtype assignments, and our own RNA-seq analysis, we found overexpression of GATA3 and FOXA1 cooperate with PPAR? activation to drive transdifferentiation of a basal bladder cancer cells to a luminial phenotype. In summary, our analysis identified a set of human cell lines suitable for the study of molecular subtypes in bladder cancer, and furthermore indicates a cooperative regulatory network consisting of GATA3, FOXA1, and PPAR? drive luminal cell fate.

SUBMITTER: Warrick JI

PROVIDER: S-EPMC5141480 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Publications

FOXA1, GATA3 and PPARɣ Cooperate to Drive Luminal Subtype in Bladder Cancer: A Molecular Analysis of Established Human Cell Lines.

Warrick Joshua I JI Walter Vonn V Yamashita Hironobu H Chung Eunah E Shuman Lauren L Amponsa Vasty Osei VO Zheng Zongyu Z Chan Wilson W Whitcomb Tiffany L TL Yue Feng F Iyyanki Tejaswi T Kawasawa Yuka I YI Kaag Matthew M Guo Wansong W Raman Jay D JD Park Joo-Seop JS DeGraff David J DJ

Scientific reports 20161207

Discrete bladder cancer molecular subtypes exhibit differential clinical aggressiveness and therapeutic response, which may have significant implications for identifying novel treatments for this common malignancy. However, research is hindered by the lack of suitable models to study each subtype. To address this limitation, we classified bladder cancer cell lines into molecular subtypes using publically available data in the Cancer Cell Line Encyclopedia (CCLE), guided by genomic characterizati ...[more]

PMID: 27924948

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Project description:Estrogen Receptor (ESR1) drives growth in the majority of human breast cancers by binding to regulatory elements and inducing transcription events that promote tumor growth. Differences in enhancer occupancy by ESR1, contribute to the diverse expression profiles and clinical outcome observed in breast cancer patients. GATA3 is an ESR1 co-operating transcription factor mutated in breast tumors, however its genomic properties are not fully defined. In order to investigate the composition of enhancers involved in estrogen-induced transcription and the potential role of GATA3, we performed extensive ChIP-sequencing in unstimulated breast cancer cells and following estrogen treatment. We find that GATA3 is pivotal in mediating enhancer accessibility at regulatory regions involved in ESR1-mediated transcription. GATA3 silencing resulted in a global redistribution of co-factors and active histone marks prior to estrogen stimulation. These global genomic changes altered the ESR1 binding profile that subsequently occurred following estrogen, with events exhibiting both loss and gain in binding affinity, implying a GATA3 mediated re-distribution of ESR1 binding. The GATA3-mediated re-distributed ESR1 profile correlated with changes in gene expression, suggestive of its functionality. Chromatin loops at the TFF locus involving ESR1 bound enhancers occurred independently of ESR1 when GATA3 was silenced, indicating that GATA3, when present on the chromatin, may serve as a licensing factor for estrogen- ESR1 mediated interactions between cis-regulatory elements. Together these experiments suggest that GATA3 directly impacts ESR1 enhancer accessibility and may potentially explain the contribution of mutant-GATA3 in the heterogeneity of ESR1+ breast cancer. MCF7 cells were transfected with siRNA and cultured in hormone deprived conditions for a further 3 days. Cells were subsequently treated with 100nM estrogen (E2) or control (Veh) for 6 hrs. We performed two independent biological experiments each using three different siRNAs against GATA3 individually (six siGATA3 replicates in total). For siControl we used RNA from five biological replicates.

Dataset Information

FOXA1, GATA3 and PPAR? Cooperate to Drive Luminal Subtype in Bladder Cancer: A Molecular Analysis of Established Human Cell Lines.

Publications

FOXA1, GATA3 and PPARɣ Cooperate to Drive Luminal Subtype in Bladder Cancer: A Molecular Analysis of Established Human Cell Lines.

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