Crosstalk between Estrogen and TNFalpha in MCF-7 Breast Cancer Cells
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE11467 | GEO | 2008/12/01
SECONDARY ACCESSION(S): PRJNA106387
REPOSITORIES: GEO
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Project description:Study was carried out to examine how E2 and TNFa together influence gene expression in breast cancer cells compared to either factor alone. Experiment Overall Design: MCF-7 cells were treated with 10 nM E2, 10 ng/ml TNFa, or both for 2h. Experiment was carried out in triplicate.
2009-01-13 | E-GEOD-11467 | biostudies-arrayexpress
Project description: Not available
| S-ECPF-GEOD-11467 | biostudies-other
Project description:We report changes in ER and GR binding profiles genome-wide upon co-treatment with Dex and E2 when compared to Dex or E2 treatments alone.
2013-07-01 | GSE46123 | GEO
Project description:Despite the success of the aromatase inhibitors (AIs) in treating estrogen receptor positive breast cancer, 15-20% of patients receiving adjuvant AIs will relapse within 5-10 years of treatment initiation. Long term estrogen deprivation (LTED) of breast cancer cells in culture has been successfully used to mimic AI-induced estrogen depletion to dissect mechanisms of AI resistance. However, we hypothesized that a subset of patients receiving AI therapy may maintain low circulating concentrations of estrogens that influence the development of endocrine resistance. We sought to expand established LTED models to account for these observations. MCF-7 cells were grown in medium with charcoal stripped serum supplemented with defined concentrations of E2 or the estrogenic androgen metabolite 3βAdiol. Cells were selected in the EC10 and EC90 of E2 or 3βAdiol, or estrogen deprived. Estrogen-independence was evaluated during selection by assessing cell growth in the absence or presence of E2 or 3βAdiol. Following >7 months of selection, estrogen-independence developed in estrogen-deprived cells and cells maintained in low concentrations of steroid hormone. Functional analyses demonstrated that estrogen-deprived and low-steroid selected cells developed estrogen-independence via unique mechanisms, independent and dependent of ERα, respectively. Estrogen-independent growth in low-steroid selected cells could be blocked by kinase inhibitors. However, these cells were completely resistant to kinase inhibition in the presence of low steroid hormone concentrations. These data offer a novel perspective on the development of resistance to AI therapy, and may yield novel approaches to treat AI-resistant tumors.
2012-03-30 | GSE33287 | GEO
Project description:We report changes in ER and GR binding profiles genome-wide upon co-treatment with Dex and E2 when compared to Dex or E2 treatments alone. We examine ER and GR binding under four different treatments (unt, Dex, E2, and Dex + E2).
2013-07-01 | E-GEOD-46123 | biostudies-arrayexpress
Project description:Despite the success of the aromatase inhibitors (AIs) in treating estrogen receptor positive breast cancer, 15-20% of patients receiving adjuvant AIs will relapse within 5-10 years of treatment initiation. Long term estrogen deprivation (LTED) of breast cancer cells in culture has been successfully used to mimic AI-induced estrogen depletion to dissect mechanisms of AI resistance. However, we hypothesized that a subset of patients receiving AI therapy may maintain low circulating concentrations of estrogens that influence the development of endocrine resistance. We sought to expand established LTED models to account for these observations. MCF-7 cells were grown in medium with charcoal stripped serum supplemented with defined concentrations of E2 or the estrogenic androgen metabolite 3βAdiol. Cells were selected in the EC10 and EC90 of E2 or 3βAdiol, or estrogen deprived. Estrogen-independence was evaluated during selection by assessing cell growth in the absence or presence of E2 or 3βAdiol. Following >7 months of selection, estrogen-independence developed in estrogen-deprived cells and cells maintained in low concentrations of steroid hormone. Functional analyses demonstrated that estrogen-deprived and low-steroid selected cells developed estrogen-independence via unique mechanisms, independent and dependent of ERα, respectively. Estrogen-independent growth in low-steroid selected cells could be blocked by kinase inhibitors. However, these cells were completely resistant to kinase inhibition in the presence of low steroid hormone concentrations. These data offer a novel perspective on the development of resistance to AI therapy, and may yield novel approaches to treat AI-resistant tumors. MCF-7 cells were selected for >7months in IMEM+10% Charcoal Stripped FBS, supplmented with defined steroid hormone conditions. Following outgrowth of estrogen-independent cells, cell lines were grown in estrogen-free conditions and gene expression analysis was performed to identify drivers of estrogen-independent growth. Cells were assessed in biological triplicates.
2012-03-29 | E-GEOD-33287 | biostudies-arrayexpress
Project description:The emergence of anti-estrogen resistance in breast cancer is an important clinical phenomenon affecting long-term survival in this disease. Identifying factors that convey cell survival in this setting may guide improvements in treatment. Estrogen (E2) can induce apoptosis in breast cancer cells that have been selected for survival after E2 deprivation for long periods (MCF-7:5C cells), but the mechanisms underlying E2-induced stress in this setting have not been elucidated. Here, we report that the c-Src kinase functions as a key adapter protein for the estrogen receptor (ER, ESR1) in its activation of stress responses induced by E2 in MCF-7:5C cells. E2 elevated phosphorylation of c-Src, which was blocked by 4-hydroxytamoxifen (4-OHT), suggesting that E2 activated c-Src through the ER. We found that E2 activated the sensors of the unfolded protein response (UPR), IRE1α (ERN1) and PERK kinase (EIF2AK3), the latter of which phosphorylates eukaryotic translation initiation factor-2α (eIF2α). E2 also dramatically increased reactive oxygen species production and upregulated expression of heme oxygenase HO-1 (HMOX1), an indicator of oxidative stress, along with the central energy sensor kinase AMPK (PRKAA2). Pharmacologic or RNA interference-mediated inhibition of c-Src abolished the phosphorylation of eIF2α and AMPK, blocked E2-induced ROS production, and inhibited E2-induced apoptosis. Together, our results establish that c-Src kinase mediates stresses generated by E2 in long-term E2-deprived cells that trigger apoptosis. This work offers a mechanistic rationale for a new approach in the treatment of endocrine-resistant breast cancer.
2014-07-18 | GSE59535 | GEO
Project description:The emergence of anti-estrogen resistance in breast cancer is an important clinical phenomenon affecting long-term survival in this disease. Identifying factors that convey cell survival in this setting may guide improvements in treatment. Estrogen (E2) can induce apoptosis in breast cancer cells that have been selected for survival after E2 deprivation for long periods (MCF-7:5C cells), but the mechanisms underlying E2-induced stress in this setting have not been elucidated. Here, we report that the c-Src kinase functions as a key adapter protein for the estrogen receptor (ER, ESR1) in its activation of stress responses induced by E2 in MCF-7:5C cells. E2 elevated phosphorylation of c-Src, which was blocked by 4-hydroxytamoxifen (4-OHT), suggesting that E2 activated c-Src through the ER. We found that E2 activated the sensors of the unfolded protein response (UPR), IRE1? (ERN1) and PERK kinase (EIF2AK3), the latter of which phosphorylates eukaryotic translation initiation factor-2? (eIF2?). E2 also dramatically increased reactive oxygen species production and upregulated expression of heme oxygenase HO-1 (HMOX1), an indicator of oxidative stress, along with the central energy sensor kinase AMPK (PRKAA2). Pharmacologic or RNA interference-mediated inhibition of c-Src abolished the phosphorylation of eIF2? and AMPK, blocked E2-induced ROS production, and inhibited E2-induced apoptosis. Together, our results establish that c-Src kinase mediates stresses generated by E2 in long-term E2-deprived cells that trigger apoptosis. This work offers a mechanistic rationale for a new approach in the treatment of endocrine-resistant breast cancer. MCF-7:5C cells were treated with vehicle (0.1% EtOH) as control, E2 (10-9mol/L), 4-OHT (10-6mol/L), E2 (10-9mol/L) plus 4-OHT (10-6mol/L), PP2 (5x10-6mol/L), and E2 (10-9mol/L) plus PP2 (5x10-6mol/L) respectively for 72 hours.
2014-07-18 | E-GEOD-59535 | biostudies-arrayexpress
Project description:MCF-7:PF is a a new in vitro model of antihormone resistant breast cancer that exhibits the characteristics of acquired tamoxifen resistance in vivo. It is well known that estrogen (E2) induces apoptosis in long-term estrogen-deprived breast cancer cells, MCF-7:5C (PubMed References PMID:15862958, PMID:16333030). MCF-7:PF was derived from MCF-7:5C through inhibition of c-Src, which blocks E2-induced apoptosis, coverts E2 responses from apoptosis to proliferation. MCF-7:PF cell growth is stimulated by E2 and SERMS in an ERα-dependent manner. Abstract: A c-Src inhibitor blocks estrogen (E2)-induced stress and converts E2 responses from inducing apoptosis to stimulating growth in E2-deprived breast cancer cells. A resulting cell line, MCF-7:PF, is reprogrammed with features of functional estrogen receptor (ER) and over-expression of insulin-like growth factor-1 receptor beta (IGF-1Rβ). We addressed the question of whether the antiestrogenic selective ER modulator 4-hydroxytamoxifen (4-OHT) could target ER to prevent E2-stimulated growth in MCF-7:PF cells. Unexpectedly, 4-OHT stimulated cell growth in an ER-dependent manner. However, unlike E2, 4-OHT suppressed classic ER-target genes as does the pure antiestrogen ICI 182,780, even during growth stimulation. Chromatin-immunoprecipitation (ChIP) assay indicated that 4-OHT did not recruit ER or nuclear receptor coactivator 3 (SRC3) to the promoter of ER-target gene, pS2. Paradoxically, 4-OHT reduced total IGF-1Rβ but increased phosphorylation of IGF-1Rβ, which was responsible for the activation of the phosphatidylinositol-3 kinases (PI3K)/Akt signaling pathway. Mechanistic studies revealed that 4-OHT rapidly activated the non-genomic pathway through ER, but other membrane-associated proteins such as IGF-1Rβ and c-Src participated. Furthermore, 4-OHT was more potent than E2 to up-regulate membrane remodeling molecules and activated focal adhesion molecules to promote cell growth. Therefore, disruption of membrane-associated signaling completely abolished 4-OHT-stimulated cell growth, but not E2-stimulated cell growth. Despite continued suppression of classic ER-target genes, 4-OHT activated the complex network of cytoskeleton remodeling and extracellular matrix-related signaling which facilitated 4-OHT-stimulated cell growth. This study is the first to recapitulate a cellular model in vitro of acquired tamoxifen (TAM) resistance developed in athymic mice in vivo.
2014-07-14 | GSE54171 | GEO
Project description:A series of MCF-7 variants were previously developed that are estrogen-dependent for growth (MCF-7:WS8 cells), or resistant to estrogen deprivation/vulnerable to fast (MCF-7:5C) and delayed (MCF-7:2A) E2-inducible apoptosis. To identify miRNAs associated with aromatase inhibitor (AI)-resistance and vulnerability to E2-induced apoptosis, estrogen deprivation-resistant 5C and 2A cells were compared to estrogen-dependent WS8 cells and among each other.
2017-03-01 | GSE79326 | GEO