The regulation of the estrogenic responses may be influenced by the
proteins that associate with
estrogen receptors (ERs) rather than solely with the receptors themselves.
ERbeta is expressed in blood vessels and may play an important role in
vascular disease. We hypothesized that specific
proteins interact with
ERbeta to modulate its response to
estrogens. By means of a yeast two hybrid screen, we discovered that NM23-H2, a multi-faceted
protein associates specifically with
ERbeta. NM23-H2 and
ERbeta consistently co-localize in a variety of human tissues (e.g. breast tissue), whereas
ERalpha and NM23-H2 did not co-localize.
Estrogen response element-mediated transcription increased by 97% when NM23-H2 and
ERbeta were over-expressed in MCF-7 cells (p< or =0.001). Moreover, there was a synergistic effect of NM23-H2 over-expression with
estrogen treatment on the reduction of MCF-7 cell migration (p< or =0.001). These results suggest that NM23-H2 associates with
ERbeta and is capable of modulating
estrogen-induced gene transcription, as well as cell migration. Hence, NM23-H2 may play an important role in modulating the response to endogenous and exogenous
estrogens, perhaps even within the context of
vascular disease.