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Fibronectin and type IV collagen activate ERα AF-1 by c-Src pathway: effect on breast cancer cell motility

2004; Springer Nature; Volume: 23; Issue: 55 Linguagem: Inglês

10.1038/sj.onc.1208098

1476-5594

Diego Sisci, Saveria Aquila, Emilia Middea, Mariaelena Gentile, Marcello Maggiolini, Fabrizia Mastroianni, Daniela Montanaro, Sebastiano Andò,

HER2/EGFR in Cancer Research

The expression of estrogen receptor alpha (ERα) is generally associated with a less invasive and aggressive phenotype in breast carcinoma. In an attempt to understand the role of ERα in regulating breast cancer cells invasiveness, we have demonstrated that cell adhesion on fibronectin (Fn) and type IV Collagen (Col) induces ERα-mediated transcription and reduces cell migration in MCF-7 and in MDA-MB-231 cell lines expressing ERα. Analysis of deleted mutants of ERα indicates that the transcriptional activation function (AF)-1 is required for ERα-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 ERα 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 ERα-mediated transcription and partially reverts the inhibition of cell invasiveness in ERα-positive cancer cells. These findings address the integrated role of ECM proteins and ERα in influencing breast cancer cell motility through a mechanism that involves c-Src and seems not to be related to a specific cell type.