Transient over-expression of estrogen receptor-α in breast cancer cells promotes cell survival and estrogen-independent growth

Tolhurst, Robert S.; Thomas, Ross S; Kyle, Fiona; Patel, Hetal; Periyasamy, Manikandan; Φωτίου, Α.; Thiruchelvam, Paul; Lai, Chun‐Fui; Al-Sabbagh, Marwa; Fisher, Rosemary A.; Barry, Sayka; Crnogorac‐Jurčević, Tatjana; Martin, Lesley-Ann; Dowsett, Mitch; Coombes, R. Charles; Kamalati, Tahereh; Ali, Simak; Buluwela, Laki

doi:10.1007/s10549-010-1122-6

Cited by 22 publications

(22 citation statements)

References 39 publications

(39 reference statements)

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“…With genomic and nongenomic actions affecting proliferation, migration, and apoptosis, the ERa has a central role in the biology of breast cancer. Indeed, prior studies have demonstrated that the ERa can protect breast cancer cells from program-induced cell death, in part, by modulating the expression of apoptosisrelated genes, such as BCL2, BIK, and BMF (16,38,39). Whereas very few of the well-established ERa-target genes (i.e., GREB1, TFF1, CCND1, etc.)…”

Section: Discussionmentioning

confidence: 99%

“…Genes whose transcript levels were increased by emetine treatment potentially contained a nonsense mutation and were prioritized on the basis of those that aligned to regions of LOH or deletion as assayed by genotyping with singlenucleotide polymorphisms (SNP) arrays. Using this strategy, we identified and further established the AT-rich interactive domain 1a (ARID1A) as a candidate tumor-suppressor gene in breast cancer, a finding that has since been confirmed by the discovery of ARID1A mutations in breast tumors by several groups (16,18). Similarly, we identified an insertion/truncation mutation at nucleotide 1184 in the SPEN gene and LOH at the SPEN locus (chromosome 1p36), resulting in undetectable SPEN protein levels in the ERa-positive, T47D breast cancer cell line (Supplementary Fig.…”

Section: Spen Is Mutated and Underexpressed In Breast Tumorsmentioning

confidence: 95%

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The Estrogen Receptor Cofactor SPEN Functions as a Tumor Suppressor and Candidate Biomarker of Drug Responsiveness in Hormone-Dependent Breast Cancers

et al. 2015

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The treatment of breast cancer has benefitted tremendously from the generation of estrogen receptor-a (ERa)-targeted therapies, but disease relapse continues to pose a challenge due to intrinsic or acquired drug resistance. In an effort to delineate potential predictive biomarkers of therapy responsiveness, multiple groups have identified several uncharacterized cofactors and interacting partners of ERa, including Split Ends (SPEN), a transcriptional corepressor. Here, we demonstrate a role for SPEN in ERa-expressing breast cancers. SPEN nonsense mutations were detectable in the ERa-expressing breast cancer cell line T47D and corresponded to undetectable protein levels. Further analysis of 101 primary breast tumors revealed that 23% displayed loss of heterozygosity at the SPEN locus and that 3% to 4% harbored somatically acquired mutations. A combination of in vitro and in vivo functional assays with microarray-based pathway analyses showed that SPEN functions as a tumor suppressor to regulate cell proliferation, tumor growth, and survival. We also found that SPEN binds ERa in a ligand-independent manner and negatively regulates the transcription of ERa targets. Moreover, we demonstrate that SPEN overexpression sensitizes hormone receptor-positive breast cancer cells to the apoptotic effects of tamoxifen, but has no effect on responsiveness to fulvestrant. Consistent with these findings, two independent datasets revealed that high SPEN protein and RNA expression in ERa-positive breast tumors predicted favorable outcome in patients treated with tamoxifen alone. Together, our data suggest that SPEN is a novel tumor-suppressor gene that may be clinically useful as a predictive biomarker of tamoxifen response in ERa-positive breast cancers. Cancer Res; 75(20); 4351-63. Ó2015 AACR.

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Section: Discussionmentioning

confidence: 99%

Section: Spen Is Mutated and Underexpressed In Breast Tumorsmentioning

confidence: 95%

The Estrogen Receptor Cofactor SPEN Functions as a Tumor Suppressor and Candidate Biomarker of Drug Responsiveness in Hormone-Dependent Breast Cancers

et al. 2015

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“…The breast cancer cell lines CAL51 (German Resource Centre for Biological Material, DSMz, Braunschweig, Germany) and MCF7 (European Collection of Cell Cultures, Health Protection Agency, UK) were grown in low glucose (1 g/l) Dulbecco's modified Eagle's medium (DMEM)-GlutaMax (Invitrogen, Carlsbad, CA, USA) supplemented with 10% foetal calf serum (FCS). Drug-resistant derivatives CALDOX, MCFDOX and MLET5 have been previously described (16)(17)(18). RNA from MDA-MB-231, T47D, zR75 and 226-L-U19 cells (19) was a generous gift from Y. zhou.…”

Section: Methodsmentioning

confidence: 99%

“…Then we examined whether TRIAP1 was associated with a drugresistance phenotype. For this, we tested TRIAP1 mRNA expression in two doxorubicin-resistant breast cancer cell lines derived from CAL51 (16) and MCF7 (17) cells, and in a third cell line derived from MCF7 cells after estrogen deprivation, which are resistant to tamoxifen and etoposide (18). Doxorubicin and etoposide are two topoisomerase II inhibitors producing genotoxic stress, ultimately leading to apoptosis, which form part of many chemotherapeutic cancer regimes.…”

Section: Triap1 Is Ubiquitously Expressed In Normal Human Tissues Andmentioning

confidence: 99%

Apoptosis inhibitor TRIAP1 is a novel effector of drug resistance

et al. 2015

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Abstract. TP53-regulated inhibitor of apoptosis 1 (TRIAP1) is a novel apoptosis inhibitor that binds HSP70 in the cytoplasm and blocks the formation of the apoptosome and caspase-9 activation. TRIAP1 has been shown to be upregulated in many types of cancers; however, its role remains elusive. We determined the TRIAP1 mRNA levels in a panel of human tissues and found its expression to be ubiquitous. Normal breast, as well as non-tumorigenic breast cells, exhibited lower TRIAP1 mRNA levels than breast cancer cells or their drug-resistant derivatives. TRIAP1 is a small, evolutionarily conserved protein that is 76 amino acids long. We found that yeast cells, in which the TRIAP1 homologue was knocked out, had increased sensitivity to doxorubicin. Equally, RNA interference in breast cancer drug-resistant cells demonstrated that downregulation of TRIAP1 impaired cell growth in the presence of doxorubicin. As expected, caspase-9 activation was diminished after overexpression of TRIAP1 in drug-resistant cells. Importantly, stable transfections of a TRIAP1 expression plasmid in CAL51 cells led to a marked increase in the number of doxorubicin-resistant clones, that was abolished when cells expressed hairpins targeting TRIAP1. In addition, we showed that TRIAP1 expression was also triggered by estrogen deprivation in MCF-7 cells. Although both polyclonal and monoclonal antibodies generated for the present study failed to robustly detect TRIAP1, we demonstrated that TRIAP1 represents a novel marker for drug resistance in breast cancer cells and it may be used in the stratification of breast cancer patients once a suitable antibody has been developed. Equally, these studies open potential drug development strategies for blocking TRIAP1 activity and avoiding drug resistance.

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“…The role of ERα in breast cancer development has been extensively investigated. Transient over-expression of ERα promotes cell survival and estrogen-independent growth [6] whereas ERα knock-down induces cell apoptosis and growth inhibition [7] in estrogen-responsive MCF-7 breast cancer cells. Recent research also indicates that estrogen-independent ERα signaling and its interaction with growth factor receptors contribute to endocrine resistance in breast cancer treatment [8].…”

Section: Introductionmentioning

confidence: 99%

Down-regulation of estrogen receptor-alpha and rearranged during transfection tyrosine kinase is associated with withaferin a-induced apoptosis in MCF-7 breast cancer cells

Zhang

Mukerji

Samadi

et al. 2011

BMC Complement Altern Med

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BackgroundWithaferin A (WA), a naturally occurring withanolide, induces apoptosis in both estrogen-responsive MCF-7 and estrogen-independent MDA-MB-231 breast cancer cell lines with higher sensitivity in MCF-7 cells, but the underlying mechanisms are not well defined. The purpose of this study was to determine the anti-cancer effects of WA in MCF-7 breast cancer cells and explore alterations in estrogen receptor alpha (ERα) and its associated molecules in vitro as novel mechanisms of WA action.MethodsThe effects of WA on MCF-7 viability and proliferation were evaluated by 3-(4, 5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay and trypan blue exclusion assays. Apoptosis was evaluated by Annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI) flow cytometry and Western blot analysis of poly (ADP-ribose) polymerase (PARP) cleavage. Cell cycle effects were analyzed by PI flow cytometry. Western blotting was also conducted to examine alterations in the expression of ERα and pathways that are associated with ERα function.ResultsWA resulted in growth inhibition and decreased viability in MCF-7 cells with an IC50 of 576 nM for 72 h. It also caused a dose- and time-dependent apoptosis and G2/M cell cycle arrest. WA-induced apoptosis was associated with down-regulation of ERα, REarranged during Transfection (RET) tyrosine kinase, and heat shock factor-1 (HSF1), as well as up-regulation of phosphorylated p38 mitogen-activated protein kinase (phospho-p38 MAPK), p53 and p21 protein expression. Co-treatment with protein synthesis inhibitor cycloheximide or proteasome inhibitor MG132 revealed that depletion of ERα by WA is post-translational, due to proteasome-dependent ERα degradation.ConclusionsTaken together, down-regulation of ERα, RET, HSF1 and up-regulation of phospho-p38 MAPK, p53, p21 are involved in the pro-apoptotic and growth-inhibitory effects of WA in MCF-7 breast cancer cells in vitro. Down-regulation of ERα protein levels by WA is caused by proteasome-dependent ERα degradation.

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Transient over-expression of estrogen receptor-α in breast cancer cells promotes cell survival and estrogen-independent growth

Cited by 22 publications

References 39 publications

The Estrogen Receptor Cofactor SPEN Functions as a Tumor Suppressor and Candidate Biomarker of Drug Responsiveness in Hormone-Dependent Breast Cancers

The Estrogen Receptor Cofactor SPEN Functions as a Tumor Suppressor and Candidate Biomarker of Drug Responsiveness in Hormone-Dependent Breast Cancers

Apoptosis inhibitor TRIAP1 is a novel effector of drug resistance

Down-regulation of estrogen receptor-alpha and rearranged during transfection tyrosine kinase is associated with withaferin a-induced apoptosis in MCF-7 breast cancer cells

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