CONICET | Buscador de Institutos y Recursos Humanos

Progesterone contributes to carcinogenesis of breast cancer. However, the role of progesterone in breast cancer cell metastasis remains obsecure. Previously we showed that progestins stimulate breast cancer cell migration and invasion, which is triggered by the activation of actin-binding protein moesin and the ensuing formation of protrusions such as pseudopodia and lamellipodium, one initial step of the whole process of cell movement. In the present study, we further investigated the effects of progestrone on the formation of focal adhension complexes, the structure formed in the wake of protrusions to provide anchors for cell attachments to extracellular matrix. Our findings showed that in T47-D breast cancer cells, progesterone rapidly enhances focal adhesion kinase (FAK) phosphorylation at Try-397 in a time- and concentration-dependent manner. As a result, exposure to progesterone leads to increased focal adhesion complexes formation concentrating at the cell periphery. The extracellular small GTPase RhoA/Rho-associated kinase (ROCK-2) cascade plays important role in progesterone-induced FAK phosphorylation. Progesterone drives progesterone receptor to interact with tyrosine kinase c-Src, which recruits phosphatidylinositol-3 kinase/Akt, leading to activation of the RhoA/ROCK-2. In the presence of progesterone, T47-D breast cancer cells display enhanced horizontal migration and invasion of three-dimensional matrices, which is markedly reversed by the trasfection with FAK small interfering RNA. In conclusion, our findings manifest that progesterone promotes breast cancer cell movement by facilitating the formation of focal adhesion complexes, which is mediated by FAK activation.

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