All @entity1968 modulates survival signaling in dormant XXXX cells.

@entity4878 @entity0 @entity5 @entity584 @entity540 @entity3 @entity236 @entity8946 @entity35466 @entity1968
UNASSIGNED: 654 Background: At the time of diagnosis, early stages of @entity0 already have microscopic @entity3 in the bone marrow. These @entity3 are resistant to adjuvant chemotherapy. The mechanisms of this resistance are not understood. In a model we developed, @entity540 ( @entity540 ), present in large deposits in the bone @entity236 , inhibits proliferation of well-differentiated @entity0 cells and induces a state of dormancy. In turn, @entity540 also induces an increased expression of integrins a5 and b1. Through these integrins, the cells bind @entity8946 and activate survival signaling through the PI3 kinase/ @entity584 pathway. Disruption of this signaling may induce cell death in the dormant cells or render them susceptible to cytotoxic therapy. @entity4878 , that have reported activity against @entity5 cells, have been shown to modulate @entity584 phosphorylation. METHODS: We investigated the role of all @entity1968 (ATRA) in inhibiting @entity584 activation in dormant clones and their survival. Two well-differentiated @entity0 cell lines, MCF-7 and T-47D were used in the studies. Cells were incubated with @entity540 10 ng/ml in @entity8946 -coated tissue culture plates at clonogenic densities and ATRA was added at variable concentrations after three days in culture for an additional three or six days. Colonies of 2-10 cells (dormant clones) were counted and lysates were analyzed by Western blot. RESULTS: @entity540 upregulated the expression of integrins a5 and b1 on Western blots after three and six days and increased the phosphorylation of @entity584 and its downstream target @entity35466 /beta. Incubation of the dormant cells with ATRA 10(-9), 10(-8) and 10(-7) M resulted in the inhibition of @entity540 -induced @entity584 phosphorylation. ATRA did not affect the increased expression of integrins a5 and b1 suggesting that this was not the mechanisms of inhibition of @entity584 phosphorylation. ATRA also inhibited the survival of dormant clones in a dose dependent manner and induced a distressed appearance in the remaining cells. CONCLUSIONS: These data suggest that ATRA, which is currently being tested in clinical trials in @entity0 , may have a potential value in the treatment of resistant micrometastases. No significant financial relationships to disclose.
