Epidermal growth factor receptor (EGFR) transactivation by estrogen via the G-protein-coupled receptor, GPR30: a novel signaling pathway with potential significance for breast cancer

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Abstract

The biological and biochemical effects of estrogen have been ascribed to its known receptors, which function as ligand-inducible transcription factors. However, estrogen also triggers rapid activation of classical second messengers (cAMP, calcium, and inositol triphosphate) and stimulation of intracellular signaling cascades mitogen-activated protein kinase (MAP K), PI3K and eNOS. These latter events are commonly activated by membrane receptors that either possess intrinsic tyrosine kinase activity or couple to heterotrimeric G-proteins. We have shown that estrogen transactivates the epidermal growth factor receptor (EGFR) to MAP K signaling axis via the G-protein-coupled receptor (GPCR), GPR30, through the release of surface-bound proHB-EGF from estrogen receptor (ER)-negative human breast cancer cells [Molecular Endocrinology 14 (2000) 1649]. This finding is consistent with a growing body of evidence suggesting that transactivation of EGFRs by GPCRs is a recurrent theme in cell signaling. GPCR-mediated transactivation of EGFRs by estrogen provides a previously unappreciated mechanism of cross-talk between estrogen and serum growth factors, and explains prior data reporting the EGF-like effects of estrogen. This novel mechanism by which estrogen activates growth factor-dependent signaling and its implications for breast cancer biology are discussed further in this review.

Introduction

Estrogens induce diverse physiological effects. Their actions are required for normal development and growth of female reproductive tissues and in certain cases, promote the growth of tumors that arise from these tissues. In addition to their impact on female reproductive tissue, estrogens regulate bone integrity [1], cardiovascular function [2] and the central nervous system [3]. These physiological and pathophysiological responses are manifested by specific receptors whose identity has important implications for human health and disease. However, the fact that estrogens promote a multitude of biochemical actions, some of which occur within seconds, others of which are measured over several hours, indicates that more than one class of receptor may participate in estrogen signaling.

The first known receptor for estrogen, termed estrogen receptor (ER), was described based on its specific binding activity in extracts prepared from rat uterus and vagina [4]. Since then its protein sequence has been determined [5] and its three-dimensional molecular structure resolved [6]. Based on its homology to receptors for other steroid hormones, the ER is classified as a member of the steroid hormone receptor (SHR) superfamily, which collectively functions as hormone-inducible transcription factors [7]. Transcriptional activity of the ER is regulated by allosteric alterations in its structure induced by estrogen and cofactors that associate with the ER. The molecular details concerning cis and trans regulation of ER functionality have been reviewed elsewhere [8], [9]. Further complexity regarding ER signaling has been provided by the discovery of ER-related proteins. The first of these to be described, ERβ, was isolated from human prostate tissue and has also been shown to facilitate estrogen-mediated gene transcription [10]. Last year, a third, more distantly related member of the ER family, ERγ, was cloned in teleosts [11]. This newest member of the ER family exhibits an expression pattern distinct from that observed for ERα and ERβ [11]. These findings provide evidence that at least three SHRs may act in concert to promote the effects of estrogen.

It has long been suspected that other receptors, distinct from the ER, may participate in estrogen signaling. This theory is borne from the observation that in addition to its ability to promote gene transcription, estrogen stimulates classical second messengers, including cAMP [12], [13], inositol phosphate [14], and calcium [15], [16]. More recently, it has been shown that estrogen also triggers signaling cascades typically linked to membrane receptors that possess tyrosine kinase activity or couple to heterotrimeric G-proteins, such as mitogen-activated protein kinase (MAP K) [17], [18], [19], phosphatidylinositiol 3-OH kinase and AKT/protein kinase B [20], [21], [22]. These latter effects of estrogen occur more rapidly (within seconds to minutes) than gene transcription events that are attributed to the ER (over the course of several hours). Moreover, unlike ER-mediated gene transcription, estrogen-induced second messenger signaling is insensitive to inhibitors of gene transcription. Due to the fact that heterotrimeric G-proteins have been shown to be required for estrogen-induced second messenger activation, others have proposed that estrogen may signal via a G-protein-coupled receptor (GPCR) [23], [24], [25]. Still others have provided evidence that ER-related proteins are associated with rapid estrogen signaling from the plasma membrane and this topic has been reviewed elsewhere [26], [27].

Section snippets

Background and historical perspective

Both estrogen and EGF are required for the growth and survival of estrogen responsive tissues. While these extracellular stimuli are structurally distinct, they exert physiological effects that overlap. For instance, both estrogen and EGF act as potent mitogens for cells from mammary epithelia and uterine endometrium [28]. However, the receptors that mediate the effects of estrogen and EGF utilize seemingly divergent signaling mechanisms. The proliferative effects of estrogen are primarily

Significance for breast cancer biology

Estrogen induces EGF-like effects in vivo [28] and prior data has indicated that the EGFR may be a vehicle for estrogen action. Approximately, a decade ago, it was demonstrated that intrauterine administration of estradiol resulted in increased concentrations of EGF [40] and EGFR autophosphorylation [41]. Further, evidence of a relationship between the EGFR and estrogen was provided by data showing that neutralizing antibodies to EGF inhibited estrogen-mediated proliferation in the uterus [73].

Conclusions

Estrogen triggers rapid activation of classical second messengers and intracellular signaling events that lie downstream of EGFRs. The recent recognition that GPCRs transduce signals, in parallel, which stimulate second messengers and activate EGFRs, suggests that GPCRs are well-suited as candidates to facilitate nongenomic estrogen signaling. Our data demonstrates that the orphan receptor GPR30 may serve such a role. We have reported that independent of ERα and ERβ, estrogen transactivates the

Acknowledgements

This work was supported in part by the T.J. Martell Foundation and a career development award from the Department of Defense. BC990477. The author wishes to express his gratitude to the members of his laboratory and especially to A. Raymond Frackelton Jr. for many helpful discussions.

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