Fibronectin and type IV collagen activate ERalpha AF-1 by c-Src pathway: effect on breast cancer cell motility.
The expression of estrogen receptor alpha (ERalpha) is generally associated with a less invasive and aggressive phenotype in breast carcinoma. In an attempt to understand the role of ERalpha in regulating breast cancer cells invasiveness, we have demonstrated that cell adhesion on fibronectin (Fn) and type IV Collagen (Col) induces ERalpha-mediated transcription and reduces cell migration in MCF-7 and in MDA-MB-231 cell lines expressing ERalpha. Analysis of deleted mutants of ERalpha indicates that the transcriptional activation function (AF)-1 is required for ERalpha-mediated transcription as well as for the inhibition of cell migration induced by cell adhesion on extracellular matrix (ECM) proteins. In addition, the nuclear localization signal region and some serine residues in the AF-1 of the ERalpha are both required for the regulation of cell invasiveness as we have observed in HeLa cells. It is worth noting that c-Src activation is coincident with adhesion of cells to ECM proteins and that the inhibition of c-Src activity by PP2 or the expression of a dominant-negative c-Src abolishes ERalpha-mediated transcription and partially reverts the inhibition of cell invasiveness in ERalpha-positive cancer cells. These findings address the integrated role of ECM proteins and ERalpha in influencing breast cancer cell motility through a mechanism that involves c-Src and seems not to be related to a specific cell type.
Sisci
Diego
D
Dipartimento Farmaco-Biologico, Università della Calabria, Arcavacata di Rende, Italy.
Aquila
Saveria
S
Middea
Emilia
E
Gentile
Mariaelena
M
Maggiolini
Marcello
M
Mastroianni
Fabrizia
F
Montanaro
Daniela
D
Andò
Sebastiano
S
D021581:Active Transport, Cell Nucleus; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism*; D000081247:CSK Tyrosine-Protein Kinase; D002402:Cathepsin D / Q000378:metabolism; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D002467:Cell Nucleus / Q000378:metabolism; D024141:Collagen Type IV / Q000737:chemistry* / Q000502:physiology*; D003600:Cytosol / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000737:chemistry* / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism; D005353:Fibronectins / Q000737:chemistry* / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D008024:Ligands; D008156:Luciferases / Q000378:metabolism; D010770:Phosphotransferases / Q000378:metabolism*; D010957:Plasmids / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D020218:Response Elements; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D015854:Up-Regulation; D019061:src-Family Kinases
D024141:Collagen Type IV; D047628:Estrogen Receptor alpha; D004967:Estrogens; D005353:Fibronectins; D008024:Ligands; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D008156:Luciferases; D010770:Phosphotransferases; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human; D002402:Cathepsin D