Extra-Nuclear Signaling of Progesterone Receptor to Breast Cancer Cell Movement and Invasion through the Actin Cytoskeleton

Abstract

Progesterone plays a role in breast cancer development and progression but the effects on breast cancer cell movement or invasion have not been fully explored. In this study, we investigate the actions of natural progesterone and of the synthetic progestin medroxyprogesterone acetate (MPA) on actin cytoskeleton remodeling and on breast cancer cell movement and invasion. In particular, we characterize the nongenomic signaling cascades implicated in these actions. T47-D breast cancer cells display enhanced horizontal migration and invasion of three-dimensional matrices in the presence of both progestins. Exposure to the hormones triggers a rapid remodeling of the actin cytoskeleton and the formation of membrane ruffles required for cell movement, which are dependent on the rapid phosphorylation of the actin-regulatory protein moesin. The extra-cellular small GTPase RhoA/Rho-associated kinase (ROCK-2) cascade plays central role in progesterone- and MPA-induced moesin activation, cell migration and invasion. In the presence of progesterone, progesterone receptor A (PRA) interacts with the G protein Gα13, while MPA drives PR to interact with tyrosine kinase c-Src and to activate phosphatidylinositol-3 kinase, leading to the activation of RhoA/ROCK-2. In conclusion, our findings manifest that progesterone and MPA promote breast cancer cell movement via rapid actin cytoskeleton remodeling, which are mediated by moesin activation. These events are triggered by RhoA/ROCK-2 cascade through partially differing pathways by the two compounds. These results provide original mechanistic explanations for the effects of progestins on breast cancer progression and highlight potential targets to treat endocrine-sensitive breast cancers.

Proteomic Analysis of Potential Breast Cancer Biomarkers

“…As such, these proteins might have the potential to be putative breast cancer markers. As expected, some well-known breast cancer markers, such as 14-3-3 proteins (Danes et al, 2008), annexins (Cao et al, 2008a), calmodulin (Gallo et al, 2008), anterior gradient homolog 2 (AGR-2) (Zweitzig et al, 2007;Fritzsche et al, 2006), Galectin-1 (Jung et al, 2007) and Rho-associated protein kinase-2 (ROCK2) (Fu et al, 2008b), were also identified in this 2D-DIGE experiment, lending credence to the reliability of early phase biomarker detection using this experimental strategy. Fig.…”

Activity of the multikinase inhibitor dasatinib against ovarian cancer cells

“…Caveolins are membrane proteins involved in receptor-independent endocytosis and can be upregulated during epithelial-to-mesenchymal transition (Bailey and Liu, 2008). Moesin, a member of the ezrin/radixin/moesin family of actinbinding proteins, cross-links the actin cytoskeleton to the plasma membrane (Rosenblatt, 2008) and recent data suggest that cell movement through rapid actin cytoskeleton remodelling is mediated by moesin activation (Fu et al, 2008). Thus, high expression of these two markers that are involved in cell adhesion and migration may characterise a cell phenotype that is particularly susceptible to Src inhibition.…”

Progesterone receptor enhances breast cancer cell motility and invasion via extranuclear activation of focal adhesion kinase

“…The small GTPase RhoA and its downstream effector ROCK-2 play a central role in regulating the actin cytoskeleton by delivering upstream signaling events to actin-regulatory proteins such as moesin or FAK (Torsoni et al 2005, Fu et al 2008b). Treatment of T47-D cells with progesterone increased the amount of active, GTP-bound RhoA (Fig.…”