Unknown,Transcriptomics,Genomics,Proteomics

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Effect of estradiol and tamoxifen on SPEN-expressing and control T47D cells.

ABSTRACT: Split Ends (SPEN) is a transcriptional coregulator that have formerly identified as a tumour suppressor gene in ER-positive breast cancers. However, ER-positive breast cancers are diagnosed at similar frequencies in pre- and post-menopausal women who show significantly different circulating hormone levels. This therefore raises the possibility that SPEN functions under hormone-depleted settings may contrast with its roles in the presence of hormones. We therefore attempted to explore the cellular functions regulated by SPEN under hormone-depleted settings using a previously established model with T47D cells stably transfected with a control vector (non-target) or SPEN-expressing vector. In particular, we attempted to investigate the hormone-independent transcriptional program regulated by SPEN in breast cancer. To achieve this, we have treated previously established T47D cells stably transfected with a control vector (non-target) or SPEN-expressing vector. These cells were allowed to grow in hormone-depleted conditions for 4 days. To minimize external biases introduced by hormone depletion or any transcriptional contribution from the estrogen receptor (ER), we also performed gene expression profiling analyses on the same cells but stimulated with an estrogen receptor (ER) agonist (Estradiol) or antagonist (Tamoxifen).

ORGANISM(S): Homo sapiens

SUBMITTER: StÃ©phanie LÃ©garÃ©

PROVIDER: E-MTAB-4975 | 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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Effect of estradiol and tamoxifen on SPEN-expressing and control T47D cells.

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