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Unliganded progesterone receptors attenuate taxane-induced breast cancer cell death by modulating the spindle assembly checkpoint

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Abstract

Whether the presence of steroid receptors in luminal breast cancers renders them resistant to taxanes remains uncertain. Here we assess the role of progesterone receptors (PR) on taxane-induced cell death. We previously showed that estrogen receptor (ER)-positive human breast cancer cells that inducibly express PR-A or PR-B isoforms were protected from taxane-stimulated apoptosis when compared to the identical cells lacking PR. Surprisingly, PR-dependent protection occurred in the absence of progesterone, demonstrating that the unliganded receptors were biologically active. The present studies demonstrate that unliganded PR, focused on PR-A, protect breast cancer cells from taxane-stimulated apoptosis. The studies identify genes regulated by taxanes in isogenic ER-positive cells that either lack or express PR-A. We show that unliganded PR-A alters the gene expression pattern controlled by taxanes, especially multiple genes involved in the spindle assembly checkpoint, a group of proteins that insure proper attachment of microtubules to kinetochores during mitosis. Importantly, taxanes and unliganded PR regulate many of these genes in opposite directions. As a result, mitotic slippage is exacerbated by the presence of PR, leading to an increase in the number of multinucleated cells both in vitro and in xenograft tumors. We describe a simple new assay for assessing multinucleation in paraffin sections. We speculate that rather than inducing cell death, unliganded PR exploits multinucleation to promote cell survival from taxane therapy. This can be prevented with antiprogestin.

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Acknowledgments

Supported by the Department of Defense Breast Cancer Research Program BC0610503 (B.M.J.), and the National Cancer Institute CA026869-31, the Avon Foundation for Women, the Breast Cancer Research Foundation, and the National Foundation for Cancer Research (K.B.H.). Supported in part by the Gene Expression, Real-time PCR and Flow Cytometry Cores of the University of Colorado Cancer Center (P30 CA046934) and by the Advanced Light Microscopy Core. We thank Toni Mufford of the animal care facility for tail-vein injections and Robert W. Burke for helpful discussions.

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The authors have no conflict of interest and nothing to disclose.

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Authors and Affiliations

  1. Program in Reproductive Sciences, Department of Obstetrics/Gynecology, University of Colorado, Anschutz Medical Campus, 12801 East 17th Avenue, Aurora, CO, 80045, USA

    Melanie M. Badtke, Monique A. Spillman, Kathryn B. Horwitz & Britta M. Jacobsen

  2. Division of Endocrinology, Department of Medicine, University of Colorado, Anschutz Medical Campus, 12801 East 17th Avenue, Aurora, CO, 80045, USA

    Melanie M. Badtke, Purevsuren Jambal, Wendy W. Dye, Kathryn B. Horwitz & Britta M. Jacobsen

  3. Department of Pathology, University of Colorado, Anschutz Medical Campus, 12801 East 17th Avenue, Aurora, CO, 80045, USA

    Miriam D. Post & Kathryn B. Horwitz

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  1. Melanie M. Badtke
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10549_2011_1399_MOESM4_ESM.tif

Supplemental Figure S1- Y iA cells inducibly express PR-A in the absence or presence of docetaxel. Immunoblot of cells treated with vehicle or pon-A to induce PR expression, with or without docetaxel. Beta-actin is shown as a loading control

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Badtke, M.M., Jambal, P., Dye, W.W. et al. Unliganded progesterone receptors attenuate taxane-induced breast cancer cell death by modulating the spindle assembly checkpoint. Breast Cancer Res Treat 131, 75–87 (2012). https://doi.org/10.1007/s10549-011-1399-0

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