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The anti-proliferative effects of progestins in T47D breast cancer cells are tempered by progestin-induction of the ETS transcription factor Elf5.

ABSTRACT: Prolactin and progesterone act together to regulate mammary alveolar development, and both hormones have been implicated in breast cancer initiation and progression. Here we show that Elf5, a prolactin-induced ETS transcription factor that specifies the mammary secretory cell lineage, is also induced by progestins in breast cancer cells via a direct mechanism. To define the transcriptional response to progestin elicited via Elf5 we made an inducible Elf5 sh-RNA knock down model in T47D breast cancer cells and used it to prevent the progestin-induction of Elf5. Functional analysis of Affymetrix gene expression data using Gene Ontologies and Gene Set Enrichment Analysis showed enhancement of the progestin effects on cell cycle gene expression. Cell proliferation assays showed a more efficacious progestin-induced growth arrest when Elf5 was kept at baseline levels. These results showed that progestin-induction of Elf5 expression tempered the anti-proliferative effects of progestins in T47D cells, providing a further mechanistic link between prolactin and progestin in the regulation of mammary cell phenotype.

ORGANISM(S): Homo sapiens

PROVIDER: GSE22363 | GEO | 2010/06/17

SECONDARY ACCESSION(S): PRJNA127673

REPOSITORIES: GEO

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The anti-proliferative effects of progestins in T47D breast cancer cells are tempered by progestin-induction of the ETS transcription factor Elf5.

Project description:Prolactin and progesterone act together to regulate mammary alveolar development, and both hormones have been implicated in breast cancer initiation and progression. Here we show that Elf5, a prolactin-induced ETS transcription factor that specifies the mammary secretory cell lineage, is also induced by progestins in breast cancer cells via a direct mechanism. To define the transcriptional response to progestin elicited via Elf5 we made an inducible Elf5 sh-RNA knock down model in T47D breast cancer cells and used it to prevent the progestin-induction of Elf5. Functional analysis of Affymetrix gene expression data using Gene Ontologies and Gene Set Enrichment Analysis showed enhancement of the progestin effects on cell cycle gene expression. Cell proliferation assays showed a more efficacious progestin-induced growth arrest when Elf5 was kept at baseline levels. These results showed that progestin-induction of Elf5 expression tempered the anti-proliferative effects of progestins in T47D cells, providing a further mechanistic link between prolactin and progestin in the regulation of mammary cell phenotype. We used Affymetrix expression arrays to determine to what extent Elf5 mediated the transcriptional effects of progestins in T47D cells. We transcript profiled our inducible Elf5 hold-down model using triplicate independent experiments under three conditions: (1) treatment with ethanol vehicle only (Baseline), (2) ORG2058 treatment for 4 days (Pg), and (3) Dox and ORG2058 treatment for 4 days, (Pg-Elf5) designed to prevent the progestin-induction of Elf5 expression.

2010-07-08 | E-GEOD-22363 | biostudies-arrayexpress

Homo sapiens

Project description:The anti-proliferative effects of progestins in T47D breast cancer cells are tempered by progestin-induction of the ETS transcription factor Elf5.

| PRJNA127673 | ENA

Gene expression in response to progestin R5020

Project description:Breast cancer cell lines containing the progesterone receptor respond to progestins, altering expression of a subset of genes. In a previously published experiment of inducible knock-down of histone H1 isoforms with an shRNA-expression lentivector (GSE12299), we modified the breast cancer cell line T47D with different vectors. Here, we explored response to progestin R5020 of control cells generated with the empty shRNA-expression vector. Stable breast cancer-derived cell lines containing the empty vector for inducible shRNA expression were grown for two days in the absence of serum. Progestin R5020 or vehicle was added for 6 hours, in duplicate, and RNA was extracted for microarray hybridization.

2013-10-14 | E-GEOD-25077 | biostudies-arrayexpress

Elf5 inhibits epithelial mesenchymal transition in development and cancer metastasis through transcriptional repression of Snail2

Project description:Elf5 (or ESE-2) is an ETS transcription factor that is abundantly expressed in the mammary epithelium, where it plays a critical role in dictating cell fate and lineage choices. These changes are in part mediated by alterations in the expression and activity of critical components of the Jak/Stat pathway. While the biological function of Elf5 in mammary gland development has been well characterized, its role in breast cancer remains to be elucidated. Here we show that loss of Elf5 leads to features associated with epithelial-mesenchymal transition (EMT) in the mouse mammary gland during pregnancy and lactation. These cellular changes in Elf5-null mammary epithelia are also reflected at the molecular level by the global enrichment of EMT-related gene signatures. ELF5 is expressed in higher level in weakly metastatic breast cancer cells that retained epithelial features compared to highly metastatic cells with mesenchymal features. ELF5 knockdown in T47D breast cancer cells resulted in EMT and increased migration. Conversely, ectopic expression of Elf5 revert mesenchymal-like MDA-MB-231 cells and its lung-tropic variant LM2 to an epithelial phenotype, with reduced migration, invasion and lung metastatic abilities. Finally, we showed that Elf5 binds directly to the promoter of the EMT transcriptional factor Snail2 (Slug) and repress its expression. Taken together, these data established a novel function for Elf5 in inhibiting EMT in normal mammary epithelium and in breast cancer through direct targeting of Snail2. This SuperSeries is composed of the following subset Series: GSE32143: LM2 cell: infected with lentivirus to stably express Elf5 vs GFP GSE32144: MDA-MB-231 cell: infected with lentivirus to stably express mut-Elf5 vs WT-Elf5

2012-09-20 | E-GEOD-32150 | biostudies-arrayexpress

Gene expression in response to progestin R5020

2013-10-14 | GSE25077 | GEO

Xenografted breast epithelia reveal differences in growth stimulation among contraceptive progestins related to androgenic properties [mouse]

Project description:Hormonal contraception exposes women to different synthetic progesterone receptor (PR) agonists, progestins, and transiently increases breast cancer risk. How progestins affect the breast epithelium is poorly understood because we lack adequate models to study this. We hypothesized that individual progestins differentially affect cell proliferation in the normal breast epithelium and hence breast cancer risk. Using mouse mammary tissue ex vivo, we show that testosterone-related progestins strongly induce the PR target and mediator of PR signaling induced cell proliferation Receptor Activator of NF-κB Ligand (Rankl), previously implicated in breast carcinogenesis, whereas other progestins fail to do so. We developed xenografts of normal human breast epithelial cells (HBECSs) to the milk ducts of immunocompromised female mice and show that they remain hormone-responsive. Using HBECSs from 36 women, we show that testosterone-related progestins, desogestrel, gestodene, and levonorgestrel, induce PSA (KLK3) and promote their proliferation, whereas the anti-androgenic progestins, which have shown anti-androgenic properties in reporter assays, chlormadinone acetate and cyproterone acetate, do not. Pharmacological inhibition of the androgen receptor (AR) inhibits PR agonist and levonorgestrel-induced RANKL expression and both pharmacological and genetic AR inhibition reduce levonorgestrel-driven breast epithelial cell proliferation in vivo. Prolonged exposure to androgenic progestins elicits hyperproliferation with cytologic changes. Thus, different progestins have distinct biological activities in the breast epithelium that should be taken into account for more informed choices in hormonal contraception.

2021-05-12 | GSE155273 | GEO

Xenografted breast epithelia reveal differences in growth stimulation among contraceptive progestins related to androgenic properties [human]

2021-05-12 | GSE155272 | GEO

Elf5 inhibits epithelial mesenchymal transition in development and cancer metastasis through transcriptional repression of Snail2

2012-09-20 | GSE32150 | GEO

Low and High Dose Progestins Elicit Distinct Breast Cancer Biology

Project description:An incomplete understanding of dose-dependent progesterone receptor (PR) biology has led to the suboptimal exploitation of PR as a therapeutic target. While hormone replacement therapies (HRT) containing low-doses of synthetic progestogens (progestins) have been associated with an increased risk of breast cancer, high-dose progestin therapies have beneficial therapeutic effects in some patients with breast cancer. Herein we report that PR subcellular localization, post-trans3lational modifications, stability, chromatin binding, responsive gene expression and downstream biology differ considerably as a function of progestin concentration. Dose-dependent transcriptional profiling revealed that different concentrations of progestin elicit classic sigmoidal and/or biphasic gene induction at distinct target gene sets. Notably, when compared to high doses of progestin, low-dose treatments lead to minimal nuclear translocation of PR while supporting robust induction of a subset of target genes, indicating that PR occupancy has a complex relationship to target gene induction. Interestingly, high but not low-dose progestin treatments lead to increased phosphorylation at Ser294 and is associated with higher receptor turnover. Furthermore, while low-dose treatments stimulate cell proliferation, high-dose treatments do not result in significant cell cycle progression to S phase. Similar biphasic and sigmoidal patterns of gene induction were observed in human breast tumor explants treated with various concentrations of progestin, underscoring the need to fine tune the dosage of PR-targeting therapies. Given the wide range of medical applications of PR target therapy, our discovery of distinct dose-dependent PR biology may have important clinical implications.

2020-06-13 | GSE99986 | GEO

The ets transcription factor ELF5 suppresses the estrogen sensitive phenotype and contributes to antiestrogen resistance in luminal breast cancer. [human ChIP-Seq]

Project description:The ets transcription factor ELF5 specifies the differentiation of mammary progenitor cells to establish the milk-secreting lineage. ER- and poor prognosis basal breast cancers arise from this progenitor cell and these cancers express high levels of Elf5. Knockdown of ELF5 expression in basal breast cancer cell lines, or forced expression in luminal breast cancer cell lines, resulted in reduced cell proliferation. Transcript profiling and chromatin immunoprecipitation revealed that the transcriptional activity of ELF5 specified the gene expression patterns that distinguish basal from luminal breast cancer, including suppression of FOXA1, GATA3 and ER, key estrogen-action genes. Tamoxifen treatment of luminal MCF7 cells upregulated Elf5 expression and cells that acquired resistance to Tamoxifen became dependent on ELF5 for proliferation. ELF5 is a regulator of breast cancer cell proliferation, transcriptionally specifies the basal molecular subtype and is utilised by ER+ breast cancer cells to escape proliferative arrest caused by Tamoxifen. ChIP-Seq using an antibody to ELF5, in T47D breast carcinoma cell lines

2012-12-27 | E-GEOD-31216 | biostudies-arrayexpress

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