Increasing tripartite cooperation of ER-alpha, c-Src, and IGF-1R plays an important role in tamoxifen resistance

Abstract

11037 Background: Acquired resistance to tamoxifen is a serious therapeutic problem that limits its clinical benefit. The precise mechanisms for acquired tamoxifen resistance, however, are still not fully understood. Our prior studies suggest that enhancement interaction between growth factors and ERa was associated with development of tamoxifen resistance. Cross-talk between growth factor receptors and estrogen receptor alpha (ERa) makes this problem more complicated. We hypothesized that some other proteins may be involved in this association between two kinds receptors in the development of TAM resistance. Methods: To test our hypothesis, MCF-7 breast cancer cells were continuously treated with TAM (10–7 M) until the cells resist to tamoxifen treatment, which were named as tamoxifen resistant cells (TAM-R). Results: TAM-R cells were more sensitive to E2 and IGF-1 stimulation to express higher level phospho-MAPK than that of control cells. Inhibitory effect of AG1024 on TAM-R cells was about as 2 folds as many as that of control cells. MAPK inhibitor caused dramatic inhibition of growth of TAM-R cells. It was interestingly found that ERa translocated from nucleus to cytosol and an increased amount of ERa was co-immunoprecipitated with IGF-1R from TAM-R cells even though there was no change in the levels of these receptors compared to the control cells. c-Src was an important adapter protein between these two receptors, which increasingly combined with both IGF-1R and ERa in TAM-R cells. Pure antiestrogen ICI, AG1024/IGF-1R SiRNA, and Src family inhibitor PP2 could inhibit the interaction between IGF-1R and ERa. However, only PP2 could completely inhibit ERa translocate from nucleus to cytosol and cytoplasm membrane. Conclusions: Our results suggested that IGF-1R/MAPK signaling pathway was very important for TAM-R cells to develop resistance. c- Src was an critical elements to form a ternary complex with IGF-1R and ERa. This may be one mechanism responsible for tamoxifen resistance in breast cancer cells. No significant financial relationships to disclose.