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Changes in subcellular localisation of MI-ER1 alpha, a novel oestrogen receptor-alpha interacting protein, is associated with breast cancer progression.

ABSTRACT: The oestrogen receptor-alpha (ER alpha) plays a key role in breast development and tumorigenesis and inhibiting its activity remains a prime strategy in the treatment of ER alpha-positive breast cancers. Thus, elucidation of the molecular mechanisms responsible for regulating ER alpha activity may facilitate the design of new, more effective breast cancer therapies. The MI-ER1 alpha is a novel transcriptional repressor that contains an LXXLL motif for interaction with nuclear hormone receptors. We investigated the ability of MI-ER1 alpha to bind to ER alpha in HEK293 and MCF-7 breast carcinoma cells, using co-immunoprecipitation assays. In both cell lines, MI-ER1 alpha interacted with ER alpha in the presence and absence of oestrogen, but the interaction was stronger in the absence of ligand. Functional analysis revealed that overexpression of MI-ER1 alpha in T47D breast carcinoma cells results in inhibition of oestrogen-stimulated anchorage-independent growth, suggesting that MI-ER1 alpha may play a role in regulating breast carcinoma cell proliferation in vivo. To explore this further, we performed an immunohistochemical analysis of normal breast tissue and breast carcinoma; a total of 110 cases were examined in whole tissue sections and 771 cases were analysed in tissue microarrays. No consistent difference in the MI-ER1 alpha expression level between normal breast tissue and breast carcinoma was discernible. However, there was a dramatic shift in the subcellular localisation: nuclear MI-ER1 alpha was detectable in 75% of normal breast samples and in 77% of hyperplasia, but in breast carcinoma, only 51% of DCIS, 25% of ILC and 4% of IDC contained nuclear staining. This shift from nuclear to cytoplasmic localisation of MI-ER1 alpha during breast cancer progression suggests that loss of nuclear MI-ER1 alpha might contribute to the development of invasive breast carcinoma.

SUBMITTER: McCarthy PL

PROVIDER: S-EPMC2527822 | biostudies-literature | 2008 Aug

REPOSITORIES: biostudies-literature

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Changes in subcellular localisation of MI-ER1 alpha, a novel oestrogen receptor-alpha interacting protein, is associated with breast cancer progression.

McCarthy P L PL Mercer F C FC Savicky M W J MW Carter B A BA Paterno G D GD Gillespie L L LL

British journal of cancer 20080729 4

The oestrogen receptor-alpha (ER alpha) plays a key role in breast development and tumorigenesis and inhibiting its activity remains a prime strategy in the treatment of ER alpha-positive breast cancers. Thus, elucidation of the molecular mechanisms responsible for regulating ER alpha activity may facilitate the design of new, more effective breast cancer therapies. The MI-ER1 alpha is a novel transcriptional repressor that contains an LXXLL motif for interaction with nuclear hormone receptors. ...[more]

PMID: 18665173

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Project description:BackgroundHomeodomain interacting protein kinases (HIPKs) function as modulators of cellular stress responses and regulate cell differentiation, proliferation and apoptosis. The HIPK family includes HIPK1, HIPK2 and HIPK3, which share a similar domain structure, and the more distantly related HIPK4. Although HIPKs phosphorylate their substrates on serine or threonine residues, it was recently reported that HIPK2 depends on the autophosphorylation of a conserved tyrosine in the activation loop to acquire full catalytic activity and correct subcellular localization. In this study we addressed the question whether tyrosine autophosphorylation in the activation loop has a similar function in the other members of the HIPK family.ResultsAll HIPKs contained phosphotyrosine when expressed in HeLa cells. Catalytically inactive point mutants were not tyrosine-phosphorylated, indicating that HIPKs are dual-specificity protein kinases that autophosphorylate on tyrosine residues. HIPK point mutants lacking the conserved tyrosine residue in the activation loop showed reduced catalytic activity towards peptide and protein substrates. Analysis of these mutants revealed that HIPK1, HIPK2 and HIPK3 but not HIPK4 are capable of autophosphorylating on other tyrosines. Inhibition of tyrosine phosphatase activity by treatment with vanadate enhanced global phosphotyrosine content of HIPK1, HIPK2 and HIPK3 but did not affect tyrosine phosphorylation in the activation loop. Mutation of the activation-loop tyrosines resulted in a redistribution of HIPK1 and HIPK2 from a speckle-like subnuclear compartment to the cytoplasm, whereas catalytically inactive point mutants showed the same pattern of cellular distribution as the wild type proteins. In contrast, mutation of the activating tyrosine did not increase the low percentage of cells with extranuclear HIPK3. HIPK4 was excluded from the nucleus with no difference between the wild type kinase and the point mutants.ConclusionsThese results show that HIPKs share the mechanism of activation by tyrosine autophosphorylation with the closely related DYRK family (dual-specificity tyrosine phosphorylation regulated kinase). However, members of the HIPK family differ regarding the subcellular localization and its dependence on tyrosine autophosphorylation.

Project description:BackgroundEndocrine therapies of breast cancer are effective but ultimately fail because of the development of treatment resistance. We have previously revealed several genes leading to tamoxifen resistance in vitro by retroviral insertion mutagenesis. To understand the manner in which these genes yield tamoxifen resistance, their effects on global gene expression were studied and those genes resulting in a distinct gene expression profile were further investigated for their clinical relevance.MethodsGene expression profiles of 69 human breast cancer cell lines that were made tamoxifen resistant through retroviral insertion mutagenesis were obtained using oligonucleotide arrays and analysed with bioinformatic tools. mRNA levels of NCOR2 and CITED2 in oestrogen receptor-positive breast tumours were determined by quantitative RT-PCR. mRNA levels were evaluated for association with metastasis-free survival (MFS) in 620 patients with lymph node-negative primary breast cancer who did not receive systemic adjuvant therapy, and with clinical benefit in 296 patients receiving tamoxifen therapy for recurrent breast cancer.ResultsmRNA expression profiles of most tamoxifen-resistant cell lines were strikingly similar, except for the subgroups of cell lines in which NCOR2 or CITED2 were targeted by the retrovirus. Both NCOR2 and CITED2 mRNA levels were associated with MFS, that is, tumour aggressiveness, independently of traditional prognostic factors. In addition, high CITED2 mRNA levels were predictive for a clinical benefit from first-line tamoxifen treatment in patients with advanced disease.ConclusionsMost retrovirally targeted genes yielding tamoxifen resistance in our cell lines do not impose a distinctive expression profile, suggesting that their causative role in cell growth may be accomplished by post-transcriptional processes. The associations of NCOR2 and CITED2 with outcome in oestrogen receptor-positive breast cancer patients underscore the clinical relevance of functional genetic screens to better understand disease progression, which may ultimately lead to the development of improved treatment options.

Dataset Information

Changes in subcellular localisation of MI-ER1 alpha, a novel oestrogen receptor-alpha interacting protein, is associated with breast cancer progression.

Publications

Changes in subcellular localisation of MI-ER1 alpha, a novel oestrogen receptor-alpha interacting protein, is associated with breast cancer progression.

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