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

• Published in: British journal of cancer 2008-08, Vol.99 (4), p.639-646
• Main Authors: McCarthy, P L, Mercer, F C, Savicky, MWJ, Carter, BA, Paterno, G D, Gillespie, L L
• Format: Article
• Language: English
• ISSN: 0007-0920
• DOI: 10.1038/sj.bjc.6604518

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-ERI alpha is a novel transcriptional repressor that contains an LXXLL motif for interaction with nuclear hormone receptors. We investigated the ability of MI-ERI alpha to bind to ER alpha in HEK293 and MCF-7 breast carcinoma cells, using co-immunoprecipitation assays. In both cell lines, MI-ERI 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-ERI alpha in T47D breast carcinoma cells results in inhibition of oestrogen-stimulated anchorage-independent growth, suggesting that MI-ERI 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-ERI alpha expression level between normal breast tissue and breast carcinoma was discernible. However, there was a dramatic shift in the subcellular localisation: nuclear MI-ERI 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-ERI alpha during breast cancer progression suggests that loss of nuclear MI-ERI alpha might contribute to the development of invasive breast carcinoma.