Extra-Nuclear Signalling of Estrogen Receptor to Breast Cancer Cytoskeletal Remodelling, Migration and Invasion

Abstract

BackgroundEstrogen is an established enhancer of breast cancer development, but less is known on its effect on local progression or metastasis. We studied the effect of estrogen receptor recruitment on actin cytoskeleton remodeling and breast cancer cell movement and invasion. Moreover, we characterized the signaling steps through which these actions are enacted.Methodology/Principal FindingsIn estrogen receptor (ER) positive T47-D breast cancer cells ER activation with 17β-estradiol induces rapid and dynamic actin cytoskeleton remodeling with the formation of specialized cell membrane structures like ruffles and pseudopodia. These effects depend on the rapid recruitment of the actin-binding protein moesin. Moesin activation by estradiol depends on the interaction of ERα with the G protein Gα13, which results in the recruitment of the small GTPase RhoA and in the subsequent activation of its downstream effector Rho-associated kinase-2 (ROCK-2). ROCK-2 is responsible for moesin phosphorylation. The Gα13/RhoA/ROCK/moesin cascade is necessary for the cytoskeletal remodeling and for the enhancement of breast cancer cell horizontal migration and invasion of three-dimensional matrices induced by estrogen. In addition, human samples of normal breast tissue, fibroadenomas and invasive ductal carcinomas show that the expression of wild-type moesin as well as of its active form is deranged in cancers, with increased protein amounts and a loss of association with the cell membrane.Conclusions/SignificanceThese results provide an original mechanism through which estrogen can facilitate breast cancer local and distant progression, identifying the extra-nuclear Gα13/RhoA/ROCK/moesin signaling cascade as a target of ERα in breast cancer cells. This information helps to understand the effects of estrogen on breast cancer metastasis and may provide new targets for therapeutic interventions.

The pancreatic β-cell as a target of estrogens and xenoestrogens: Implications for blood glucose homeostasis and diabetes

“…For instance, it may act through other transcription factors binding to their respective response elements (Dahlman-Wright et al, 2006). In addition, it has been demonstrated that extra-nuclear ER can activate protein kinases (Giretti et al, 2008;Migliaccio et al, 1996;Simoncini et al, 2000). Contrary to the results shown by Le May et al (2006) that exclusively found ER in -cell nuclei, our data indicate that in -cells, ER is located inside and outside the nucleus .…”

Gα73Β is a downstream effector of JAK/STAT signalling and a regulator of Rho1 inDrosophilahaematopoiesis

“…However, in addition to their role in canonical GPCR signalling, recent evidence suggests a more versatile role for Ga subunits. Studies from in vivo models have implicated Ga in mitotic spindle organisation (Wilkie and Kinch, 2005) and microtubule and cytoskeleton dynamics (Giretti et al, 2008). Ga proteins are also involved in the regulation of Hippo-YAP (Yu et al, 2012) signalling.…”

Cross talk between epidermal growth factor (EGF) receptor and extra nuclear steroid receptors in cell lines

“…Recent work from different laboratories shows that ERs located outside the nucleus activate different signal transduction pathways with multiple effects, such as cell growth and survival (Kousteni et al, 2001), cell migration (Giretti et al, 2008), and vasorelaxation (Simoncini et al, 2000). How can ERs, which unlike growth factor receptors are soluble and lack intrinsic enzyme activity, exert these stimulatory effects?…”

“…Inside the nucleus, these receptors interact with hundreds of proteins that in different ways regulate ER transcriptional action (O'Malley, 2005). Outside the nucleus protein/protein interactions shape the signaling pathway followed by signal transduction from membrane to cell interior (Pawson, 2007).Recent work from different laboratories shows that ERs located outside the nucleus activate different signal transduction pathways with multiple effects, such as cell growth and survival (Kousteni et al, 2001), cell migration (Giretti et al, 2008), and vasorelaxation (Simoncini et al, 2000). How can ERs, which unlike growth factor receptors are soluble and lack intrinsic enzyme activity, exert these stimulatory effects?…”