Progressive Loss of Estrogen Receptor α Cofactor Recruitment in Endocrine Resistance

Naughton, Catherine; MacLeod, Kenneth G.; Kuske, Barbara; Clarke, Robert; Cameron, David; Langdon, Simon P.

doi:10.1210/me.2007-0110

Cited by 20 publications

(19 citation statements)

References 33 publications

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“…This is in contrast to a previously described MCF-7 derived line, LCC1, generated through in vivo selection under conditions of low estrogen availability, and LCC9, derived from LCC1 following selection for growth in the presence of ICI [30]. LCC1 and LCC9 remain ERα-positive, but show reduced expression of the p160 co-activators (SRC1, TIF2 and AIB1) and the co-repressors NCoR and SMRT [31]. The elevated levels of NCoR and SMRT may explain the reduced expression of pS2, CTD and PR in MLET5 cells.…”

Section: Estrogen Receptor-α Over-expression By Adenoviral Transducticontrasting

confidence: 57%

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

Tolhurst

Thomas

Kyle

et al. 2010

Breast Cancer Res Treat

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Section: Estrogen Receptor-α Over-expression By Adenoviral Transducticontrasting

confidence: 57%

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

Tolhurst

Thomas

Kyle

et al. 2010

Breast Cancer Res Treat

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“…Like LCoR, overexpression of NRIP1 represses estrogen-dependent gene expression in transient expression studies (45). Similar to NRIP1 and LCoR, recruitment of corepressors NCoR and SMRT in the presence of estrogen was also observed on the pS2 promoter (44,47). Moreover, the association of HDACs with the pS2 promoter in the presence of estrogen has been documented (24).…”

Section: Discussionmentioning

confidence: 93%

Function of Histone Deacetylase 6 as a Cofactor of Nuclear Receptor Coregulator LCoR

Palijan

Fernandes

Bastien

et al. 2009

Journal of Biological Chemistry

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Ligand-dependent corepressor LCoR was identified as a protein that interacts with the estrogen receptor ␣ (ER␣) ligand binding domain in a hormone-dependent manner. LCoR also interacts directly with histone deacetylase 3 (HDAC3) and HDAC6. Notably, HDAC6 has emerged as a marker of breast cancer prognosis. However, although HDAC3 is nuclear, HDAC6 is cytoplasmic in many cells. We found that HDAC6 is partially nuclear in estrogen-responsive MCF7 cells, colocalizes with LCoR, represses transactivation of estrogen-inducible reporter genes, and augments corepression by LCoR. In contrast, no repression was observed upon HDAC6 expression in COS7 cells, where it is exclusively cytoplasmic. LCoR binds to HDAC6 in vitro via a central domain, and repression by LCoR mutants lacking this domain was attenuated. Kinetic chromatin immunoprecipitation assays revealed hormone-dependent recruitment of LCoR to promoters of ER␣-induced target genes in synchrony with ER␣. HDAC6 was also recruited to these promoters, and repeat chromatin immunoprecipitation experiments confirmed the corecruitment of LCoR with ER␣ and with HDAC6. Remarkably, however, although we find evidence for corecruitment of LCoR and ER␣ on genes repressed by the receptor, LCoR and HDAC6 failed to coimmunoprecipitate, suggesting that they are part of distinct complexes on these genes. Although small interfering RNA-mediated knockdown of LCoR or HDAC6 augmented expression of an estrogen-sensitive reporter gene in MCF7 cells, unexpectedly their ablation led to reduced expression of some endogenous estrogen target genes. Taken together, these data establish that HDAC6 can function as a cofactor of LCoR but suggest that they may act in enhance expressing some target genes.Nuclear receptors are ligand-regulated transcription factors whose activities are controlled by a variety of lipophilic extracellular signals, including steroid and thyroid hormones, metabolites of vitamins A (retinoids) and D (1, 2). DNA-bound nuclear receptors regulate transcription by recruiting complexes of coregulatory proteins, classified as coactivators or corepressors depending on whether they act to stimulate or repress transcription (2-4). Many coactivators interact with receptors through signature LXXLL motifs, known as NR boxes, which are oriented within a hydrophobic pocket of agonist-bound receptor ligand binding domains (5). Several coactivators or their associated cofactors possess histone acetyltransferase activity, which essentially caps positively charged lysine residues and loosens their association with DNA, facilitating chromatin remodeling and subsequent access of the transcriptional machinery to promoters.Nuclear receptor corepressors NCoR 7 and SMRT were isolated as factors that interacted with hormone-free but not hormone-bound thyroid and retinoid receptors (6, 7). They bind to receptor ligand binding domains through extended LXXX-IXXX(L/I) motifs known as CoRNR boxes (8, 9) and recruit multiprotein complexes implicated in transcriptional repression and histone deacetylatio...

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“…The mechanisms involved in resistance to endocrine therapy are diverse. For example, ER␣ transactivation in tamoxifen-resistant cell lines may depend on as yet unidentified coregulators or may be independent of the p160 coactivators (22,48).…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies show that tamoxifen-resistant breast cancer cells that retain dependence on ER␣ for growth lose their dependence on SRC3 and other p160 coactivators for E 2 -ER␣-mediated gene transcription (22,48). We explored the ability of TPSF to inhibit E 2 and OHT-dependent gene expression in tamoxifenresistant cells that are less dependent on p160 coactivators for transactivation.…”

Section: Tpsf Is a Structure-specific Inhibitor That Acts Outside Of mentioning

confidence: 99%

A Noncompetitive Small Molecule Inhibitor of Estrogen-regulated Gene Expression and Breast Cancer Cell Growth That Enhances Proteasome-dependent Degradation of Estrogen Receptor α

Kretzer

Cherian

Mao

et al. 2010

Journal of Biological Chemistry

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The mechanisms responsible for 17␤-estradiol (E 2 )-stimulated breast cancer growth and development of resistance to tamoxifen and other estrogen receptor ␣ (ER␣) antagonists are not fully understood. We describe a new tool for dissecting ER␣ action in breast cancer, p-fluoro-4-(1,2,3,6,-tetrahydro-1,3-dimethyl-2-oxo-6-thionpurin-8-ylthio) (TPSF), a potent small-molecule inhibitor of estrogen receptor ␣ that does not compete with estrogen for binding to ER␣. TPSF noncompetitively inhibits estrogen-dependent ER␣-mediated gene expression with little inhibition of transcriptional activity by NF-B or the androgen or glucocorticoid receptor. TPSF inhibits E 2 -ER␣-mediated induction of the proteinase inhibitor 9 gene, which is activated by ER␣ binding to estrogen response element DNA, and the cyclin D1 gene, which is induced by tethering ER␣ to other DNA-bound proteins. TPSF inhibits anchorage-dependent and anchorage-independent E 2 -ER␣-stimulated growth of MCF-7 cells but does not inhibit growth of ER-negative MDA-MB-231 breast cancer cells. TPSF also inhibits ER␣-dependent growth in three cellular models for tamoxifen resistance; that is, 4-hydroxytamoxifen-stimulated MCF7ER␣HA cells that overexpress ER␣, fully tamoxifen-resistant BT474 cells that have amplified HER-2 and AIB1, and partially tamoxifen-resistant ZR-75 cells. TPSF reduces ER␣ protein levels in MCF-7 cells and several other cell lines without altering ER␣ mRNA levels. The proteasome inhibitor MG132 abolished down-regulation of ER␣ by TPSF. Thus, TPSF affects receptor levels at least in part due to its ability to enhance proteasome-dependent degradation of ER␣. TPSF represents a novel class of ER inhibitor with significant clinical potential. Estrogen receptor ␣ (ER␣)3 is a well studied member of the steroid/nuclear receptor family of transcription regulators. ER␣ acts in the nucleus to regulate gene expression by binding to estrogen response elements (EREs) and related DNA sequences (1-4) and through association with transcription factors bound at SP1 and AP-1 DNA binding sites (4 -7). In response to high affinity estrogen binding, ER␣ dimerizes, binds to ERE DNAs, and undergoes a conformational change in the ligand binding domain that facilitates the recruitment of coactivators (8). Bound coactivators promote assembly of a multiprotein complex that enables chromatin remodeling and stabilization of an active transcription complex (9 -11). In contrast, antagonist-occupied ER␣ recruits corepressors (12).At detection, growth of most human breast cancers depends on 17␤-estradiol (E 2 ) binding to ER␣ (13-16). Treatment strategies that inhibit estrogen-dependent breast cancer include selective ER modulators such as tamoxifen, which binds in the ER␣ ligand binding pocket, and aromatase inhibitors, which block estrogen production. Nearly half of patients treated with aromatase inhibitors develop resistance (17). The long-term effectiveness of tamoxifen is limited by the development of resistance in nearly all patients with metastatic breast cancer and in ϳ4...

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Progressive Loss of Estrogen Receptor α Cofactor Recruitment in Endocrine Resistance

Cited by 20 publications

References 33 publications

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

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

Function of Histone Deacetylase 6 as a Cofactor of Nuclear Receptor Coregulator LCoR

A Noncompetitive Small Molecule Inhibitor of Estrogen-regulated Gene Expression and Breast Cancer Cell Growth That Enhances Proteasome-dependent Degradation of Estrogen Receptor α

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