Estrogen Receptor Alpha: Impact of Ligands on Intracellular Shuttling and Turnover Rate in Breast Cancer Cells

Abstract

Estrogen receptors (α and ß) are members of the steroid/thyroid nuclear receptors superfamily of ligand-dependent transcription factors. Impact of the α 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 five years on the mechanism of action of ER 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 mobile protein 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 second 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 transactivation. 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.

Capacity of type I and II ligands to confer to estrogen receptor alpha an appropriate conformation for the recruitment of coactivators containing a LxxLL motif—Relationship with the regulation of receptor level and ERE-dependent transcription in MCF-7 cells

“…Although the underlying mechanism has not been investigated as yet, this observation is consistent with the existence of repeated cyclic interactions between ERα and cognate partners during target gene transactivation, a concept developed by several authors [31,42,43], is implicated in this dynamic LxxLL-coactivator recruitment is unknown. Investigating such a possibility seems to us of primary importance.…”

Calmodulin-independent, agonistic properties of a peptide containing the calmodulin binding site of estrogen receptor α

“…EREs, heat shock proteins, histone acetyltransferases of the CBP/p300 family, transcription factors, ubiquitin ligases…) (for review : Leclercq et al, 2006;Nawaz and O'Malley, 2004) we are currently investigating. Indeed, the production of such peptides may be a key determinant of the basal (ligand-independent) transcriptional activity of ER.…”

“…Studies of our laboratory are devoted to the analysis of the mechanisms by which this receptor contributes to the pathogenesis of breast tumors. ER belongs to the superfamily of nuclear receptors which are known to act as ligand-dependent transcription factors (Evans, 1988;Leclercq et al, 2006). Actually, ER biological activities are modulated by formation of diverse transient complexes with a variety of co-regulators (Rossini, 1994).…”

Calmodulin, a regulatory partner of the estrogen receptor alpha in breast cancer cells

“…The potential implication of CaM in the regulation of ERα turnover rate, and thus in the control of ERα transactivation ability (Leclercq et al, 2006), is also evoked.…”

“…This finding does not mean that ERα is sequestered within the nucleus since it has been shown to undergo a dynamic intracellular shuttling (Maruvada et al, 2003;Nonclercq et al, 2007;Stenoien et al, 2000) which seems to determine the type of response to estrogen signaling (Leclercq et al, 2006 (Acconcia, Kumar, 2006;Pedram et al, 2006;Song, 2007). In contrast, nuclear form(s) of ERα directly regulate gene expression (Nuclear Initiated Steroid Signaling, NISS), the receptor functioning in this case as an estrogen-dependent transcription factor (or as a coregulator of other transcription factors).…”