Molecular mechanism of a cross‐talk between oestrogen and growth factor signalling pathways

Abstract

Oestrogen (E 2 ) plays signi®cant roles in variety of biological events such as the development and maintenance of female reproductive organs, bone and lipid metabolisms. More recently, from study of knock-out mice de®cient in oestrogen receptor (ER) a and ERb it turned out that normal spermatogenesis requires the E 2 actions. Furthermore, this female steroid hormone is also well known to be deeply involved in many pathophysiological events such as osteoporosis and cancer development in female reproductive organs. It is particularly well known that most breast cancer is dependent on E 2 in its development. Such E 2 actions are thought to be mediated through two subtypes of ERs. Growth factors have been shown to synergize in this E 2 signalling pathway, although the actual molecular mechanism largely remains unknown.Recently, we found that the MAP kinase activated by growth factors phosphorylates the Ser 118 residue of the human ERa A/B domain and this phosphorylation potentiates the N-terminal transactivation function (AF-1) of human ERa, indicating the possible molecular mechanism of a novel cross-talk between E 2 and growth factor signalling pathways. More recently, we have identi®ed a coactivator associating with the hERa AF-1 in a MAPK-mediated phosphorylationdependent manner. In this review, the molecular mechanism of this cross-talk is discussed in terms of the transactivation function of ERs, and their coactivators.

Increased risk of malignant progression in benign proliferating breast lesions defined by expression of heat shock protein 27

“…However, this association was not maintained in normal lobules. These findings support the concept that hsp-27 is intimately linked to oestrogen action (Adams and McGuire, 1985;Thor et al, 1991;Kato et al, 2000), although the exact mechanisms of this link remain poorly understood. The observation that ER-a( þ ) tumours expressed higher levels of hsp-27, as measured by OD when compared with ER-a(À) cancers, might further suggest a prognostic role for overexpressed hsp-27 in breast cancer.…”

“…In this respect, oestrogen-associated proteins are of particular interest since this hormone plays a crucial role in regulating mammary epithelial proliferation (Buerger et al, 2001), and is recognised as promoting the malignant progression of certain neoplastic and potentially premalignant lesions (Page and Dupont, 1990). Important modulators of oestrogen, and likely mediators of this hormone's effect on breast epithelial cells, act through different receptors, including the family of homeostatic regulators known as heat shock proteins (hsp's) (Kato et al, 2000).…”

TNF-α enhances estrogen-induced cell proliferation of estrogen-dependent breast tumor cells through a complex containing nuclear factor-kappa B

“…Several nuclear receptor coactivators have been described to be involved in ER transactivation, RAC3 being one of them (McKenna et al, 1999;Kato et al, 2000;List et al, 2001;Planas-Silva et al, 2001;Hamelers and Steenbergh, 2003). This is also a coactivator for NF-kB (Werbajh et al, 2000), and it has been shown to be amplified in several ovarian and mammary tumor cells such as T47D cell line (Anzick et al, 1997).…”

Estrogen action and cytoplasmic signaling cascades. Part I: membrane-associated signaling complexes

“…Definition of the classic estrogen-signaling pathway highlighted the fact that, in many instances, another signaling pathway(s) involving cytoplasmic proteins, growth factors and/or membrane-initiated responses contributed to estrogen action (reviewed in Refs [14][15][16][17][18]). In Part I of this review, we focus on membraneassociated estrogen action, particularly cellular responses observed within minutes of estrogen exposure.…”