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

Abstract

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

Activation of the dioxin/aryl hydrocarbon receptor (AhR) modulates cell plasticity through a JNK-dependent mechanism

“…Taken together with the recent finding that ER activation contributes to inhibit cell movement in MCF7 cells (Sisci et al, 2004), this raised questions as to the generality of the AhRmediated effects documented here. However, the well-differentiated HepG2 hepatocarcinoma cells, which do not respond to estrogens, responded to AhR ligand treatment in a way similar to MCF7 cells (Supplementary Figure 3).…”

MCF‐7 human mammary adenocarcinoma cells exhibit augmented responses to human insulin on a collagen IV surface

“…Others have reported that collagen IV stimulates a variety of fundamental functions in MCF-7 cells, such as proliferation, STAT5 signaling, estrogen receptor alpha signaling, src kinase activity and matrix metalloprotease 5 secretion (Cortes-Reynosa et al, 2008;Hirtenlehne et al, 2002;Robledo et al, 2005;Sisci et al, 2004). Likewise, collagen IV specifi cally stimulated chemotaxis of MCF-7 cells towards IGF-1 (Doerr and Jones, 1996).…”

Tamoxifen treatment promotes phosphorylation of the adhesion molecules, p130Cas/BCAR1, FAK and Src, via an adhesion-dependent pathway

“…It is also clear that the subcellular localization of p130Cas is strongly correlated with migration (Fonseca et al, 2004) and in this context it is interesting to note that BCAR3/ AND-34 has been proposed to be required for localization of p130Cas at ruffling membranes (Riggins et al, 2003). Finally, it has been suggested that there may be an auto-regulatory loop between integrins-FAK-c-Src and the ER that inhibits cell migration, but in response to constitutive activation of c-Src, the effects of c-Src become dominant and promote cell migration (Sisci et al, 2004). Possibly, therefore further sustained activation of Src in MCF-7 cells following chronic exposure to tamoxifen may similarly weigh the balance in favour of a pro-migratory phenotype.…”