title: 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.
authors.affiliation: Division of BioMedical Sciences, Faculty of Medicine, Terry Fox Cancer Research Laboratories, Memorial University of Newfoundland, St John's, NL A1B 3V6, Canada.
authors.forename: P L
authors.initials: PL
authors.lastname: McCarthy
authors.forename: F C
authors.initials: FC
authors.lastname: Mercer
authors.forename: M W J
authors.initials: MW
authors.lastname: Savicky
authors.forename: B A
authors.initials: BA
authors.lastname: Carter
authors.forename: G D
authors.initials: GD
authors.lastname: Paterno
authors.forename: L L
authors.initials: LL
authors.lastname: Gillespie
mesh_terms: D000328:Adult; D000368:Aged; D015153:Blotting, Western; D001940:Breast / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000378:metabolism* / Q000473:pathology; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000378:metabolism* / Q000473:pathology; D018275:Carcinoma, Lobular / Q000378:metabolism* / Q000473:pathology; D002467:Cell Nucleus / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay; D003593:Cytoplasm / Q000378:metabolism / Q000473:pathology; D004268:DNA-Binding Proteins; D018450:Disease Progression; D004318:Doxycycline / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D004967:Estrogens / Q000494:pharmacology; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D007668:Kidney / Q000378:metabolism; D008875:Middle Aged; D009687:Nuclear Proteins / Q000378:metabolism*; D013347:Subcellular Fractions; D046888:Tissue Array Analysis; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D004967:Estrogens; C470480:MIER1 protein, human; D009687:Nuclear Proteins; D014157:Transcription Factors; D004318:Doxycycline