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: 4.91). 03/2010; 17(2):431-43. DOI: 10.1677/ERC-09-0258
Source: PubMed

ABSTRACT 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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    • "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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