Src Is an Initial Target of Sex Steroid Hormone Action

Abstract

Recent observations that steroids use pathways universally known to be regulated by growth factors and interleukins highlight the following points: (1) Steroid stimulation of the canonical pathway Src/Ras/Erk signaling from membrane to nuclei or its single members has been observed in different cell types including human cancer‐derived cells, neurons, osteoblasts, osteocytes, and endothelial cells. This stimulation has been reconstituted and analyzed in transiently transfected cells. (2) Cellular context and intracellular localization of receptors are crucial in determining the biological effects evoked by this hormonal stimulation: proliferation, protection from apoptosis, and vasorelaxation. (3) Classical steroid receptors localized in the extranuclear compartment directly and, in some cases, simultaneously interact with Src. They are capable of unexpected cross talks responsible for the observed effects. (4) Other signaling pathways including P13K/AKT are also stimulated by steroids. The aim of future work will be to arrive at an integrated general view of the different signaling pathways activated by steroids and to analyze the concert between these pathways and the hormonal transcriptional action. This general view should be simultaneously verified in different cell contexts, under different physiologic and pathologic conditions. We expect that the new technologies, above all gene and protein microarray, will make this goal feasible.

RASSF1A inhibits estrogen receptor alpha expression and estrogen-independent signalling: implications for breast cancer development

“…E2 treatment has been reported to lead to rapid and transient activation of the Ras-MAPK pathway that is thought to proceed through a multistep process involving E2-bound ERa, Src and the p85 regulatory subunit of PI3K. 11,13,47,48 In turn, Src mediates activation of matrix metalloproteinases that liberate HB-EGF bound to the surface of the MCF7 cells, leading to epidermal growth factor receptor transactivation and activation of Ras-MAPK pathway. 11 Our results are consistent with the notion that RASSF1A suppresses E2-mediated liberation of membrane-bound HB-EGF, in turn inhibiting the rapid and transient activation of the Ras-MAPK pathway (Figure 8).…”

Tamoxifen treatment promotes phosphorylation of the adhesion molecules, p130Cas/BCAR1, FAK and Src, via an adhesion-dependent pathway

“…Further, estrogen can reportedly promote the association of the ER with p130Cas and Src (Cabodi et al, 2004). However, a common feature of all of these studies is that they examine acute stimulation of ER and the responses seen were rapid and transient (Arnold et al, 1995(Arnold et al, , 1997Migliaccio et al, 2002;Pratt et al, 2005). We have examined the signalling pathways in the population of cells that are viable after 14 days of tamoxifen treatment, so it is unlikely that any of these early response mechanisms explain the results we have shown.…”

“…However, our demonstration that ICI 182, 780 gave the same effects as tamoxifen indicates that the effects we observe are due to tamoxifen antagonist effects. There is clearly a complex relationship between the ER and c-Src; c-Src can directly phosphorylate and activate the ER (Arnold et al, 1995(Arnold et al, 1997Pratt et al, 2005), whereas conversely, estrogen stimulation enhances Src activation (reviewed in Migliaccio et al, 2002). Further, estrogen can reportedly promote the association of the ER with p130Cas and Src (Cabodi et al, 2004).…”

Resistance to endocrine therapy in breast cancer: exploiting estrogen receptor/growth factor signaling crosstalk

“…Estrogenactivated membrane ER can also phosphorylate and activate the epidermal growth factor receptor (EGFR) in a process that involves activation of G-proteins, c-Src, and MMPs (Razandi et al 2003a). ER also directly associates with a plethora of other key signaling molecules such as c-Src (Migliaccio et al 2002, Shc (Song et al 2002), and the p85a regulatory subunit of PI3K (Sun et al 2001, Migliaccio et al 2002. Many of these interactions lead to the activation of key secondary signaling messengers and downstream kinase pathways, such as the p21Ras/p42/44 MAPK and AKT, leading to the activation of various cellular processes such as proliferation, growth, and survival.…”