steroids 73 ( 2 0 0 8 ) 870–873 available at www.sciencedirect.com journal homepage: www.elsevier.com/locate/steroids Association of the membrane estrogen receptor, GPR30, with breast tumor metastasis and transactivation of the epidermal growth factor receptor Edward J. Filardo a,* , Jeffrey A. Quinn a , Edmond Sabo b a Department of Medicine, Rhode Island Hospital and Brown University School of Medicine, Providence, RI 02903, USA b Department of Pathology, Rhode Island Hospital and Brown University School of Medicine, Providence, RI 02903, USA article info Published on line 3 January 2008 Keywords: GPR30 Metastasis Estrogen Integrin EGFR abstract The epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases func- tion as a common signaling conduit for membrane receptors that lack intrinsic enzymatic activity, such as G-protein coupled receptors and integrins. GPR30, an orphan member of the seven transmembrane receptor (7TMR) superfamily has been linked to specific estro- gen binding, rapid estrogen-mediated activation of adenylyl cyclase and the release of membrane-tethered proHB-EGF. More recently, GPR30 expression in primary breast ade- nocarcinoma has been associated with pathological parameters commonly used to assess breast cancer progression, including the development of extramammary metastases. This newly appreciated mechanism of cross communication between estrogen and EGF is con- sistent with the observation that 7TMR-mediated transactivation of the EGFR is a recurrent signaling paradigm and may explain prior data reporting the EGF-like effects of estrogen. The molecular details surrounding GPR30-mediated release of proHB-EGF, the involvement of integrin 1 as a signaling intermediary in estrogen-dependent EGFR action, and the possible implications of these data for breast cancer progression are discussed herein. Published by Elsevier Inc. 1. Introduction Estrogen induces diverse physiological and pathophysiologi- cal effects. Specifically, its actions are required for the growth and development of female reproductive tissues, and certain tumors that arise from these tissues. In addition, estrogen also influences bone integrity [1], cardiovascular function [2] and central nervous system function [3]. The use of estrogen ana- logues that antagonize the binding of estrogen to its known receptors, ER and ER, is an effective therapeutic strat- egy for attenuating the growth of estrogen receptor-positive breast tumors [4,5]. The growth inhibitory influence associ- ated with ER antagonism is consistent with the ability of * Corresponding author at: Rhode Island Hospital, 593 Eddy Street, Aldrich Building Room 718, Providence, RI 02903, USA. Tel.: +1 401 444 5806; fax: +1 401 444 8483. E-mail address: edward filardo@brown.edu (E.J. Filardo). these compounds to inhibit breast tumor cell proliferation in vitro. Similar therapeutic benefit is derived from using selec- tive estrogen receptor modifiers (SERMs) to treat patients with osteoporosis, although it is not yet entirely clear whether this beneficial effect is due to an inhibitory effect on osteo- clastogenesis or a stimulatory influence on osteoblasts [6]. Estrogen also promotes physiological responses that are not entirely defined by cellular mitogenesis. For instance, estro- gen action is associated with mammary gland branching [7]. Similarly, nonproliferative actions have been measured in the nervous system, including regulatory effects at monoamin- ergic neurons that influence mood and cognition [8], and in hypothalamic neurons that control energy homeostasis [9]. 0039-128X/$ – see front matter. Published by Elsevier Inc. doi:10.1016/j.steroids.2007.12.025