Unknown,Transcriptomics,Genomics,Proteomics

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The ETS transcription factor ELF5 modulates estrogen action in breast cancer via participation in FOXA1-ER driven transcription.

ABSTRACT: The ETS transcription factor ELF5 drives mammary alveolar development in preparation for lactation by forcing differentiation within the progenitor cell population. In luminal A breast cancer, early disease progression is predicted by high levels of ELF5, and in preclinical models elevated ELF5 is associated with its two key features, the acquisition of resistance to endocrine therapy and increased metastasis. We first created an MCF7 cell line with doxycycline-inducible ELF5 and then examined with ChIP-seq differences in genomic binding of FOXA1, ER and H3K4me3 upon doxycycline treatment, compared to vehicle. In addition we performed RNA-seq experiments to examine changes in gene expression upon induction of ELF5 expression. Here we demonstrate that ELF5 binding overlaps with FOXA1 and ER at enhancers and promoters, and when elevated causes FOXA1 and ER to bind to new regions of the genome involved in resistance to endocrine therapy. RNA-seq demonstrated that these changes altered gene expression to diminish estrogen influence, and that ELF5 regulated the expression of ER transcription-complex genes. These data show that ELF5 modulated estrogen-driven transcription in breast cancer by directing FOXA1 and ER to new genomic locations, and by interaction with, and regulation of, members of the ER transcriptional complex. This provides a mechanistic basis for the influence of ELF5 on the progression of luminal breast cancer to endocrine insensitivity.

INSTRUMENT(S): Illumina HiSeq 2500, Illumina HiSeq 2000

ORGANISM(S): Homo sapiens

SUBMITTER: Christopher Ormandy

PROVIDER: E-MTAB-7641 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Breast cancer is a heterogeneous disease comprised of at least five major subtypes. Luminal subtype tumors confer a more favourable patient prognosis, which is in part, attributed to the Estrogen Receptor-alpha (ER) positivity and anti-hormone responsiveness of these tumors. Expression of the forkhead box transcription factor, FOXA1, also correlates with the luminal subtype and patient survival, but is present in a subset of ER-negative tumors. Similarly, FOXA1 is consistently expressed in luminal breast cancer cell lines even in the absence of ER. In contrast, basal breast cancer cell lines do not express FOXA1, and loss of FOXA1 in luminal cells increases migration and invasion, characteristics of the basal subtype. To delineate an ER-independent role for FOXA1 in maintaining the luminal phenotype, and hence a more favourable prognosis, we performed cDNA microarray analyses on luminal FOXA1-positive, ER-positive (MCF7, T47D) and FOXA1-positive, ER-negative (MDA-MB-453, SKBR3) cell lines in the presence or absence of transient FOXA1 silencing. This resulted in three FOXA1 transcriptomes: (1) a luminal-signature (consistent across cell lines), (2) an ER-positive signature (restricted to MCF7 and T47D) and (3) an ER-negative signature (restricted to MDA-MB-453 and SKBR3). Use of Gene Set Enrichment Analyses (GSEA) as a phenotyping tool revealed that FOXA1 silencing resulted in a transcriptome shift from luminal to basal gene expression signatures. FOXA1 binds to both luminal and basal genes within luminal breast cancer cells, suggesting that it not only transactivates luminal genes, but also represses basal-associated genes. From these results we conclude that FOXA1 controls plasticity between basal and luminal cells, playing a dominant role in repressing the basal phenotype, and thus tumor aggressiveness, in luminal breast cancer cells. Although it has been proposed that FOXA1-targeting agents may be useful for treating luminal tumors, these data suggest that this approach may promote transitions toward a more aggressive cancer. FOXA1 siRNA treated breast cell lines compared directly to nonspecific siRNA treated cell lines using Agilent 4X44 microarrays.

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The ETS transcription factor ELF5 modulates estrogen action in breast cancer via participation in FOXA1-ER driven transcription.

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