SRC1 gene regulation in endocrine resistant breast cancer cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: McCartan D
PROVIDER: S-ECPF-GEOD-28645 | biostudies-other | 2012 Jan
REPOSITORIES: biostudies-other
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Project description:The development of breast cancer resistance to endocrine therapy results from an increase in cellular plasticity leading to the development of a steroid independent tumour. The p160 steroid coactivator protein SRC-1, through interactions with developmental proteins and other non-steroidal transcription factors drives this tumour adaptability. Here, using discovery studies we identify ADAM22, a non-protease member of the ADAMs family, as a direct target of SRC-1, independent of estrogen receptor(ER). Molecular, cellular, in vivo and clinical studies confirmed SRC-1 as a regulator of ADAM22 and established a role for ADAM22 in endocrine resistant tumour progression. ADAM22 has the potential to act as a therapeutic drug target and a companion predictive biomarker in the treatment of endocrine resistant breast cancer. 14 samples representing 4 conditions were analysed. Samples were transfected with either a siRNA targetting SRC1 or a control scrambled siRNA. Samples were subject to tamoxifen treatment or untreated.
2012-01-11 | E-GEOD-28645 | biostudies-arrayexpress
Project description:The development of breast cancer resistance to endocrine therapy results from an increase in cellular plasticity leading to the development of a steroid independent tumour. The p160 steroid coactivator protein SRC-1, through interactions with developmental proteins and other non-steroidal transcription factors drives this tumour adaptability. Here, using discovery studies we identify ADAM22, a non-protease member of the ADAMs family, as a direct target of SRC-1, independent of estrogen receptor(ER). Molecular, cellular, in vivo and clinical studies confirmed SRC-1 as a regulator of ADAM22 and established a role for ADAM22 in endocrine resistant tumour progression. ADAM22 has the potential to act as a therapeutic drug target and a companion predictive biomarker in the treatment of endocrine resistant breast cancer.
2012-01-11 | GSE28645 | GEO
Project description:Reduced COUP-TFII expression contributes to endocrine resistance in breast cancer cells. Endocrine-resistant breast cancer cells have higher NFkappa B (NF?B) activity and target gene expression. The goal of this study was to determine if COUP-TFII modulates NF?B activity. Endocrine-resistant LCC9 cells with low endogenous COUP-TFII displayed ?5-fold higher basal NF?B activity than parental endocrine-sensitive MCF-7 breast cancer cells. Transient transfection of LCC9 cells with COUP-TFII inhibited NF?B activation and reduced NF?B target gene expression. COUP-TFII and NF?B were inversely correlated in breast cancer patient samples. Endogenous COUP-TFII coimmunoprecipitated with NF?B subunits RelB and NF?B1 in MCF-7 cells. COUP-TFII inhibited NF?B-DNA binding in vitro and impaired coactivator induced NF?B transactivation. LCC9 cells were growth-inhibited by an NF?B inhibitor and 4-hydroxytamoxifen compared to MCF-7 cells. Together these data indicate a novel role for COUP-TFII in suppression of NF?B activity and explain, in part, why decreased COUP-TFII expression results in an endocrine-resistant phenotype.
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Project description:BackgroundEndocrine treatment is one of the most effective therapies for estrogen receptor-positive breast cancer. However, most tumors will develop resistance to endocrine therapy as the cancer progresses. This review focuses on the mechanisms and markers of endocrine-resistant breast cancer. In addition, current and future strategies to overcome endocrine resistance are discussed.SummarySeveral molecular mechanisms of endocrine resistance have been identified, including alterations in the ESR1 gene or in the PIK3CA/mTOR pathway. Meanwhile, CDK4/6, mTOR, and PI3K inhibition have shown to improve the efficacy of endocrine treatment and new promising approaches are being developed.Key messageOvercoming primary or acquired resistance to endocrine treatment remains a major challenge. Since the molecular mechanisms of endocrine resistance are manifold, optimal combination and sequencing strategies will have to be developed in the future.
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Project description:The Notch pathway is functionally important in breast cancer. Notch-1 has been reported to maintain an estrogen-independent phenotype in estrogen receptor α (ERα)+ breast cancer cells. Notch-4 expression correlates with Ki67. Notch-4 also plays a key role in breast cancer stem-like cells. Estrogen-independent breast cancer cell lines have higher Notch activity than estrogen-dependent lines. Protein kinase Cα (PKCα) overexpression is common in endocrine-resistant breast cancers and promotes tamoxifen (TAM)-resistant growth in breast cancer cell lines. We tested whether PKCα overexpression affects Notch activity and whether Notch signaling contributes to endocrine resistance in PKCα-overexpressing breast cancer cells.Analysis of published microarray data from ERα+ breast carcinomas shows that PKCα expression correlates strongly with Notch-4. Real-time reverse transcription PCR and immunohistochemistry on archival specimens confirmed this finding. In a PKCα-overexpressing, TAM-resistant T47D model, PKCα selectively increases Notch-4, but not Notch-1, expression in vitro and in vivo. This effect is mediated by activator protein-1 (AP-1) occupancy of the Notch-4 promoter. Notch-4 knockdown inhibits estrogen-independent growth of PKCα-overexpressing T47D cells, whereas Notch-4IC expression stimulates it. Gene expression profiling shows that multiple genes and pathways associated with endocrine resistance are induced in Notch-4IC- and PKCα-expressing T47D cells. In PKCα-overexpressing T47D xenografts, an orally active γ-secretase inhibitor at clinically relevant doses significantly decreased estrogen-independent tumor growth, alone and in combination with TAM. In conclusion, PKCα overexpression induces Notch-4 through AP-1. Notch-4 promotes estrogen-independent, TAM-resistant growth and activates multiple pathways connected with endocrine resistance and chemoresistance. Notch inhibitors should be clinically evaluated in PKCα- and Notch-4-overexpressing, endocrine-resistant breast cancers.
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Project description:Aberrant microRNA expression contributes to breast cancer progression and endocrine resistance. We reported that although tamoxifen stimulated miR-29b-1/a transcription in tamoxifen (TAM)-resistant breast cancer cells, ectopic expression of miR-29b-1/a did not drive TAM-resistance in MCF-7 breast cancer cells. However, miR-29b-1/a overexpression significantly repressed TAM-resistant LCC9 cell proliferation, suggesting that miR-29b-1/a is not mediating TAM resistance but acts as a tumor suppressor in TAM-resistant cells. The target genes mediating this tumor suppressor activity were unknown. Here, we identify miR-29b-1 and miR-29a target transcripts in both MCF-7 and LCC9 cells. We find that miR-29b-1 and miR-29a regulate common and unique transcripts in each cell line. The cell-specific and common downregulated genes were characterized using the MetaCore Gene Ontology (GO) enrichment analysis algorithm. LCC9-sepecific miR-29b-1/a-regulated GO processes include oxidative phosphorylation, ATP metabolism, and apoptosis. Extracellular flux analysis of cells transfected with anti- or pre- miR-29a confirmed that miR-29a inhibits mitochondrial bioenergetics in LCC9 cells. qPCR,luciferase reporter assays, and western blot also verified the ATP synthase subunit genes ATP5G1 and ATPIF1 as bone fide miR29b-1/a targets. Our results suggest that miR-29 repression of TAM-resistant breast cancer cell proliferation is mediated in part through repression of genes important in mitochondrial bioenergetics.
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Project description:Proteomic profiling of the estrogen/tamoxifen-sensitive MCF-7 cell line and its partially sensitive (MCF-7/LCC1) and fully resistant (MCF-7/LCC9) variants was performed to identify modifiers of endocrine sensitivity in breast cancer. Analysis of the expression of 120 paired phosphorylated and non-phosphorylated epitopes in key oncogenic and tumor suppressor pathways revealed that STAT1 and several phosphorylated epitopes (phospho-STAT1(Tyr701) and phospho-STAT3(Ser727)) were differentially expressed between endocrine resistant and parental controls, confirmed by qRT-PCR and western blotting. The STAT1 inhibitor EGCG was a more effective inhibitor of the endocrine resistant MCF-7/LCC1 and MCF-7/LCC9 lines than parental MCF-7 cells, while STAT3 inhibitors Stattic and WP1066 were equally effective in endocrine-resistant and parental lines. The effects of the STAT inhibitors were additive, rather than synergistic, when tested in combination with tamoxifen in vitro. Expression of STAT1 and STAT3 were measured by quantitative immunofluorescence in invasive breast cancers and matched lymph nodes. When lymph node expression was compared to its paired primary breast cancer expression, there was greater expression of cytoplasmic STAT1 (?3.1 fold), phospho-STAT3(Ser727) (?1.8 fold), and STAT5 (?1.5 fold) and nuclear phospho-STAT3(Ser727) (?1.5 fold) in the nodes. Expression levels of STAT1 and STAT3 transcript were analysed in 550 breast cancers from publicly available gene expression datasets (GSE2990, GSE12093, GSE6532). When treatment with tamoxifen was considered, STAT1 gene expression was nearly predictive of distant metastasis-free survival (DMFS, log-rank p?=?0.067), while STAT3 gene expression was predictive of DMFS (log-rank p<0.0001). Analysis of STAT1 and STAT3 protein expression in a series of 546 breast cancers also indicated that high expression of STAT3 protein was associated with improved survival (DMFS, p?=?0.006). These results suggest that STAT signaling is important in endocrine resistance, and that STAT inhibitors may represent potential therapies in breast cancer, even in the resistant setting.
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