Glucocorticoid-induced functional polarity of growth factor responsiveness regulates tight junction dynamics in transformed mammary epithelial tumor cells.
The synthetic glucocorticoid, dexamethasone, induces the "normal-like" differentiated property of tight junction formation and suppresses growth of the Con8 mammary epithelial tumor cell line, derived from a 7,12-dimethylbenz(alpha)anthracene-induced rat mammary adenocarcinoma. Characterization of the transepithelial electrical resistance of Con8 mammary tumor cells cultured on permeable supports revealed that a novel response to dexamethasone is the generation of a polarized cell monolayer with respect to epidermal growth factor receptor responsiveness. Administration of transforming growth factor-alpha (TGF-alpha) to the basolateral, but not the apical, plasma membrane compartment disrupted the glucocorticoid-stimulated tight junction barrier. Confocal immunofluorescence microscopy revealed that dexamethasone caused the ZO-1 tight junction-associated protein to localize exclusively to the apical border of laterally adjacent membranes of the cell periphery, whereas basolateral administration of TGF-alpha caused the redistribution of ZO-1 back to disorganized aggregates along the cell periphery. In contrast, TGF-alpha was able to exert its mitogenic effects equally on both sides of the cell monolayer independent of its polarized disruption of tight junction formation. Our results represent the first evidence for a functional polarization of the epidermal growth factor receptor and strongly implicate the glucocorticoid-regulated formation of tight junctions in policing the polarized responsiveness of mammary cells to growth factors.
D000230:Adenocarcinoma; D000818:Animals; D015153:Blotting, Western; D002461:Cell Line, Transformed; D002462:Cell Membrane / Q000187:drug effects / Q000502:physiology; D003907:Dexamethasone / Q000494:pharmacology*; D004848:Epithelium / Q000187:drug effects / Q000502:physiology; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology*; D007700:Kinetics; D008325:Mammary Neoplasms, Experimental; D008565:Membrane Proteins / Q000032:analysis / Q000096:biosynthesis / Q000502:physiology; D018613:Microscopy, Confocal; D010750:Phosphoproteins / Q000032:analysis / Q000096:biosynthesis / Q000502:physiology; D051381:Rats; D019108:Tight Junctions / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors; D016211:Transforming Growth Factor alpha / Q000494:pharmacology*; D062826:Zonula Occludens-1 Protein
D005938:Glucocorticoids; D008565:Membrane Proteins; D010750:Phosphoproteins; C569044:Tjp1 protein, rat; D016211:Transforming Growth Factor alpha; D062826:Zonula Occludens-1 Protein; D003907:Dexamethasone