PROGESTERONE ENHANCES BREAST CANCER CELL MOBILITY BY THE NON-GENOMIC ACTIVATION OF FOCAL ADHESION KINASE

L. GOGLIA; A.M. SANCHEZ; M.I. FLAMINI; M.S. GIRETTI; C. BALDACCI; S. GARIBALDI; A.R GENAZZANI; X.D. FU; T. SIMONCINI

March 4-7, FIRENZE, ITALY.

Congreso; 14th World Congress of Gynecological Endocrinology, II Congresso ISGE Italia; 2010

INTERNATIONAL SOCIETY OF GYNECOLOGICAL ENDOCRINOLOGY (ISGE)

Progesterone contributes to carcinogenesis of breast cancer. However, the role of progesterone in breast cancer cell metastasis remains obsecure. 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. These events are triggered by RhoA/ROCK-2 cascade through c-Src and PI3K/Akt pathways. Our results provide original mechanistic views for the effects of progesterone on breast cancer progression and may in the future be helpful to develop new drugs aganist endocrine-sensitive breast cancers.