Paxillin, a novel controller in the signaling of estrogen to FAK/N-WASP/Arp2/3 complex in breast cancer cells.
Breast cancer is the major cause of cancer-related death in women. Its treatment is particularly difficult when metastasis occurs. The ability of cancer cells to move and invade the surrounding environment is the basis of local and distant metastasis. Cancer cells are able to remodel the actin cytoskeleton, which requires the recruitment of numerous structural and regulatory proteins that modulate actin filaments dynamics, including Paxillin or the Neural Wiskott-Aldrich Syndrome Protein (N-WASP). We show that 17-β estradiol (E2) induces phosphorylation of Paxillin and its translocation toward membrane sites where focal adhesion complexes are assembled. This cascade is triggered by a Gαi1/Gβ protein-dependent signaling of estrogen receptor α (ERα) to c-Src, focal adhesion kinase (FAK) and Paxillin. Within this complex, activated Paxillin recruits the small GTPase Cdc42, which triggers N-WASP phosphorylation. This results in the redistribution of Arp2/3 complexes at sites where membrane structures related to cell movement are formed. Recruitment of Paxillin, Cdc42 and N-WASP is necessary for cell adhesion, migration and invasion induced by E2 in breast cancer cells. In parallel, we investigated whether Raloxifene (RAL), a selective estrogen receptor modulator (SERMs), could inhibit or revert the effects of E2 in breast cancer cell movement. We found that, in the presence of E2, RAL acts as an ER antagonist and displays an inhibitory effect on estrogen-promoted cell adhesion and migration via FAK/Paxillin/N-WASP. Our findings identify an original mechanism through which estrogen regulates breast cancer cell motility and invasion via Paxillin. These results may have clinical relevance for the development of new therapeutic strategies for cancer treatment.
Institute of Medicine and Experimental Biology of Cuyo (IMBECU), National Research Council of Argentina, Mendoza, Argentina.
Jorge Eduardo
JE
Shortrede
Institute of Medicine and Experimental Biology of Cuyo (IMBECU), National Research Council of Argentina, Mendoza, Argentina.
Ivonne Denise
ID
Uzair
Institute of Medicine and Experimental Biology of Cuyo (IMBECU), National Research Council of Argentina, Mendoza, Argentina.
Flavia Judith
FJ
Neira
Institute of Medicine and Experimental Biology of Cuyo (IMBECU), National Research Council of Argentina, Mendoza, Argentina.
Marina Inés
MI
Flamini
Institute of Medicine and Experimental Biology of Cuyo (IMBECU), National Research Council of Argentina, Mendoza, Argentina. Electronic address: amsanchez@mendoza-conicet.gov.ar.
Angel Matías
AM
Sanchez
D008841:Actin Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D051376:Actin-Related Protein 2-3 Complex / Q000378:metabolism*; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D047628:Estrogen Receptor alpha / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism*; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D044387:GTP-Binding Protein beta Subunits / Q000378:metabolism; D006801:Humans; D009361:Neoplasm Invasiveness; D051419:Paxillin / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D020849:Raloxifene Hydrochloride / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D051317:Wiskott-Aldrich Syndrome Protein, Neuronal / Q000378:metabolism*; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
D051376:Actin-Related Protein 2-3 Complex; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D004967:Estrogens; D044387:GTP-Binding Protein beta Subunits; D051419:Paxillin; C495771:WASL protein, human; D051317:Wiskott-Aldrich Syndrome Protein, Neuronal; D020849:Raloxifene Hydrochloride; D051416:Focal Adhesion Protein-Tyrosine Kinases; D019061:src-Family Kinases; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D020764:cdc42 GTP-Binding Protein
Breast cancer metastasis; Estrogen; N-WASP; Paxillin; Raloxifene