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

Department of Reproductive Medicine and Child Development, University of Pisa, Italy.
Endocrine Related Cancer (Impact Factor: 4.81). 03/2010; 17(2):431-43. DOI: 10.1677/ERC-09-0258
Source: PubMed


While progesterone plays multiple roles in the process of breast development and differentiation, its role in breast cancer is less understood. We have shown previously that progestins stimulate breast cancer cell migration and invasion because of the activation of rapid signaling cascades leading to modifications in the actin cytoskeleton and cell membrane that are required for cell movement. In this study, we have investigated the effects of progesterone on the formation of focal adhesion (FA) complexes, which provide anchoring sites for cell attachment to the extracellular matrix during cell movement and invasion. In T47-D breast cancer cells, progesterone rapidly enhances FA kinase (FAK) phosphorylation at Tyr(397) in a time- and concentration-dependent manner. As a result, exposure to progesterone leads to increased formation of FA complexes within specialized cell membrane protrusions. The cascade of events required for this phenomenon involves progesterone receptor interaction with the tyrosine kinase c-Src, which activates the phosphatidylinositol-3-kinase/Akt pathway and the small GTPase RhoA/Rho-associated kinase complex. In the presence of progesterone, T47-D breast cancer cells display enhanced horizontal migration and invasion of three-dimensional matrices, which is reversed by small interfering RNAs abrogating FAK. In conclusion, progesterone promotes breast cancer cell movement and invasion by facilitating the formation of FA complexes via the rapid regulation of FAK. These results provide novel mechanistic views on the effects of progesterone on breast cancer progression, and may in the future be helpful to develop new strategies for the treatment of endocrine-sensitive breast cancers.

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Available from: Marina Flamini, Nov 11, 2015
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    • "Notably, it has been shown that non-genomic actions of the ligand-activated PR lead to activation of the RhoA/Rho-associated kinase (ROCK-2) cascade in T47D cells [52], [62]. This signaling pathway, ultimately, directs remodeling of the actin cytoskeleton and formation of membrane ruffles required for cell movement [52]; it, also, leads to rapid activation of the focal adhesion (FA) kinase and increased formation of FA complexes, which provide anchoring sites for cell attachment to the extracellular matrix during cell movement and invasion [62]. During preparation of this manuscript a study came out that described the PR-targetome during mammary gland branching morphogenesis [63]. "
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    ABSTRACT: Despite the pleiotropic effects of the progesterone receptor in breast cancer, the molecular mechanisms in play remain largely unknown. To gain a global view of the PR-orchestrated networks, we used next-generation sequencing to determine the progestin-regulated transcriptome in T47D breast cancer cells. We identify a large number of PR target genes involved in critical cellular programs, such as regulation of transcription, apoptosis, cell motion and angiogenesis. Integration of the transcriptomic data with the PR-binding profiling of hormonally treated cells identifies numerous components of the small-GTPases signaling pathways as direct PR targets. Progestin-induced deregulation of the small GTPases may contribute to the PR's role in mammary tumorigenesis. Transcript expression analysis reveals significant expression changes of specific transcript variants in response to the extracellular hormonal stimulus. Using the NET1 gene as an example, we show that the PR can dictate alternative promoter usage leading to the upregulation of an isoform that may play a role in metastatic breast cancer. Future studies should aim to characterize these selectively regulated variants and evaluate their clinical utility in prognosis and targeted therapy of hormonally responsive breast tumors.
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    • "Magnification is represented by 100 í µí¼‡m scale in all photomicrographs. effect can occur through various mechanisms, including overexpression of proteins such as superoxide dismutase, tissue factor, and protease-activated receptors [33] [34] [35]; the enhancing of matrix metalloproteinases and urokinase-type plasminogen activator activities [36]; the activating of the focal adhesion kinase [37], and the activation of rapid signaling cascades that leads to modifications in the actin cytoskeleton and the cell membrane [38] [39]. In other several cell lines, including glioma cells, it has been found that voltage-gated ion channels play a significant role in initiation "
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    • "evale et al . , 2007 ; Castoria et al . , 1999 ; Migliaccio et al . , 2007 ; Proietti et al . , 2005 ; Saitoh et al . , 2005 ; Skildum et al . , 2005 ) . Rapid activation of the PI3K / Akt / Rho / ROCk signaling cascade in breast cancer cells has also been reported to be involved in mediating the effects of P4 on cell motility and focal adhesion ( Fu et al . , 2010 ) . The non - receptor tyrosine kinase c - Src is a central player in mediating rapid activation of signaling cascades by all steroid hormone receptors . Src is proximal in the signaling pathways af - fected , and it can bind steroid receptors either directly or indirectly ( Ballare et al . , 2003 ; Boonyaratanakornkit et al . , 2001 ) "
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