Changes in subcellular localisation of MI-ER1α, a novel oestrogen receptor-α interacting protein, is associated with breast cancer progression

Abstract

The oestrogen receptor-a (ERa) plays a key role in breast development and tumorigenesis and inhibiting its activity remains a prime strategy in the treatment of ERa-positive breast cancers. Thus, elucidation of the molecular mechanisms responsible for regulating ERa activity may facilitate the design of new, more effective breast cancer therapies. The MI-ER1a is a novel transcriptional repressor that contains an LXXLL motif for interaction with nuclear hormone receptors. We investigated the ability of MI-ER1a to bind to ERa in HEK293 and MCF-7 breast carcinoma cells, using co-immunoprecipitation assays. In both cell lines, MI-ER1a interacted with ERa in the presence and absence of oestrogen, but the interaction was stronger in the absence of ligand. Functional analysis revealed that overexpression of MI-ER1a in T47D breast carcinoma cells results in inhibition of oestrogen-stimulated anchorage-independent growth, suggesting that MI-ER1a 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-ER1a expression level between normal breast tissue and breast carcinoma was discernible. However, there was a dramatic shift in the subcellular localisation: nuclear MI-ER1a 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-ER1a during breast cancer progression suggests that loss of nuclear MI-ER1a might contribute to the development of invasive breast carcinoma.

Differential HDAC1 and 2 Recruitment by Members of the MIER Family

“…Both proteins contain contiguous ELM2-SANT domains, recruit HDACs, interact with ERα to repress its activity and both function generally as corepressors [4, 6, 22–24]. The MTA family of proteins is encoded by three genes, mta1-3 , with MTA1 being the best characterized [25].…”

“…Additional studies focused on the α isoform of MIER1, showing that it interacts with estrogen receptor α (ERα) and that stable expression of MIER1α under the control of the Tre promoter in T47D breast carcinoma cells inhibited estrogen-stimulated colony growth [6]. Immunohistochemical examination of breast tumour samples revealed a shift in the subcellular localization of MIER1α, from the nucleus to the cytoplasm, during breast cancer progression [6].…”

“…Additional studies focused on the α isoform of MIER1, showing that it interacts with estrogen receptor α (ERα) and that stable expression of MIER1α under the control of the Tre promoter in T47D breast carcinoma cells inhibited estrogen-stimulated colony growth [6]. Immunohistochemical examination of breast tumour samples revealed a shift in the subcellular localization of MIER1α, from the nucleus to the cytoplasm, during breast cancer progression [6]. While the mechanism responsible for shuttling MIER1α out of the nucleus in breast cancer patients is not known, alternative splicing to include the NES [3] or treatment of breast carcinoma cells with insulin or insulin-like growth factor 1 (IGF1) [7] were both shown to produce a similar change in subcellular localization.…”

Rat Mcs1b Is Concordant to the Genome-Wide Association-Identified Breast Cancer Risk Locus at Human 5q11.2 and MIER3 is a Candidate Cancer Susceptibility Gene

“…Human and rat MIER3/Mier3 (GenBank ref| NP_689835.3 and NP_001161472.1) gene products share 93% amino acid sequence identity, and human MIER3 and MIER1 (GenBank ref|NP_001071172.1) have 54% identical amino acids based on BLAST [42]. MIER1 physically interacts with estrogen receptor alpha, Sp1, and Creb-binding protein [50–52]. MIER1 contains one, while MIER3 has two conserved LXXLL sequences, which is a motif that facilitates nuclear hormone receptor interactions [53].…”

Characteristics of peri‐implantation porcine concepti population and maternal milieu influence the transcriptome profile

“…Glucocorticoids, unlike progesterone, also seem to regulate trophoblast differentiation and association with the endometrium (Malassiné and Cronier, 2002). The MIER1 protein in non‐trophoblastic epithelial cells works at the receptor level where it can sequester E2 receptor α and limit E2 activity (McCarthy et al, 2008). In the human trophoblast, TGFβ1 can regulate E2 synthesis and initiate its terminal differentiation (Croniera et al, 1999; Rama et al, 2004).…”