Tamoxifen and ICI 182,780 increase Bcl-2 levels and inhibit growth of breast carcinoma cells by modulating PI3K/AKT, ERK and IGF-1R pathways independent of ERalpha.

We recently showed that estrogen withdrawal from the ERalpha(+), high Bcl-2-expressing breast carcinoma cells (MCF-7B) reduced Bcl-2 protein levels while increasing cell-cell adhesion, and junction formation. Here we compared these cells with the ERalpha(+) and low Bcl-2-expressing MCF-7 cells and with the normal mammary epithelial cell line MCF-10-2A not expressing ERalpha or Bcl-2. All cell lines expressed normal HER2. Antiestrogen (Tamoxifen and ICI 182,780) treatment increased Bcl-2 levels in both MCF-7 and -7B cells and led to the formation of acinar structures. This treatment led to the dissociation of junctions and redistribution of junctional components to the cytoplasm in MCF-10-2A and -7 cells, while in MCF-7B cells junctional proteins redistributed to membranes. Antiestrogen treatment decreased PI3K/Akt activation and increased ERK activation regardless of ERalpha status. IGF-1R was inactivated in the antiestrogen-treated MCF-7 cells while it was activated in MCF-7B cells. Our data show that Tamoxifen and ICI 182,780 can induce growth inhibitory effects via the sustained activation/inactivation of signaling pathways that regulate cell survival, cell death and differentiation in the absence of ERalpha. Furthermore, Bcl-2 overexpression may alter the functional interactions among these pathways in response to antiestrogens, which also may provide a potential explanation for the observation that Bcl-2 overexpressing tumors have a better prognosis.