Estrogen receptor alpha: impact of ligands on intracellular shuttling
and turnover rate in breast cancer cells.
by Guy Leclercq, Marc Lacroix, Ioanna Laïos, Guy Laurent
Jean-Claude Heuson Breast Cancer Laboratory, Institut Jules Bordet
Institute, Bruxelles (Brussels) and Histology and Experimental Cytology
Laboratory, University of Mons-Hainaut, Belgique (Belgium)
in Current Cancer Drug Targets (2006) 6, 39-64
http://www.geocities.com/m.lacroix/ccdt1.htm
Estrogen receptors (alpha and beta) are members of the steroid/thyroid
nuclear receptors super-family of ligand-dependent transcription
factors. Impact of the alpha isoform of estrogen receptor (ER) on
breast cancer etiology and progression is now well established. Current
therapeutic strategy to treat ER-positive breast cancer relies on the
blockade of ER trancriptional activity by antiestrogens. Data
accumulated during the last years on ER mechanism of action enable one
to foresee new strategies. These data indeed reveal that ER is not
statically bound to DNA at promoter sites of genes regulating cell
proliferation and/or differentiation, but rather behaves as a very
mobileprotein continuously shuttling between targets located within
various cellular compartments (i.e. membrane, microsomes, nucleus...).
This allows the receptor to generate both non-genomic and genomic
responses. Ligands, growth factors and 2nd messengers produced
downstream of activated membrane receptors modulate ER-mediated
responses by interfering with the traffic patterns of the receptor, as
well as by locally blocking its transient anchorage. Changes in ER
turnover rate associated with these regulatory processes seem also to
strongly influence the ability of the receptor to mediate gene
trans-activation. The present paper surveys these biological data and
analyzes how they may be integrated into new drug design programs aimed
at expanding our therapeutic armamentarium against breast cancer.
