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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 ERα

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Abstract

We recently showed that estrogen withdrawal from the ERα+, 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 ERα+ and low Bcl-2-expressing MCF-7 cells and with the normal mammary epithelial cell line MCF-10-2A not expressing ERα 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 ERα 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 ERα. 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.

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Acknowledgments

We are grateful to Kim Chapman and Drs. E. Shibuya, J. Mackey and R. Campenot for their critical review of the manuscript. This project has been made possible through grants from the Canadian Breast Cancer Foundation- PRAIRIES/NWT Chapter, and Alberta Cancer Foundation.

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  1. Department of Cell Biology, University of Alberta, 6-24 Medical Sciences Building, Edmonton, AB, Canada, T6G 2H7

    Le Lam, Xiuying Hu, Zackie Aktary & Manijeh Pasdar

  2. Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada

    David W. Andrews

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  1. Le Lam
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Correspondence to Manijeh Pasdar.

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L. Lam and X. Hu contributed equally to this work.

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10549_2008_231_MOESM1_ESM.jpg

Levels of the apoptosis regulating proteins in MCF-10-2A, -7, -7B and cultures treated with estrogen antagonists. Total cellular levels of Bcl-2, Bad, Bax and Bim and tubulin were determined by Western blot of the total cell lysates from control and drug-treated cultures of MCF-10-2A, -7 and -7B as described in Materials and methods. Histograms were generated by normalizing the amount of each protein to the amount of tubulin detected in the same extract sample relative to the untreated lysates (JPG 66 kb)

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Lam, L., Hu, X., Aktary, Z. et al. 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 ERα. Breast Cancer Res Treat 118, 605–621 (2009). https://doi.org/10.1007/s10549-008-0231-y

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