title: Unliganded progesterone receptors attenuate taxane-induced breast cancer cell death by modulating the spindle assembly checkpoint.
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.
authors.affiliation: Program in Reproductive Sciences, Department of Obstetrics/Gynecology, University of Colorado, Anschutz Medical Campus, 12801 East 17th Avenue, Aurora, CO 80045, USA.
authors.forename: Melanie M
authors.initials: MM
authors.lastname: Badtke
authors.forename: Purevsuren
authors.initials: P
authors.lastname: Jambal
authors.forename: Wendy W
authors.initials: WW
authors.lastname: Dye
authors.forename: Monique A
authors.initials: MA
authors.lastname: Spillman
authors.forename: Miriam D
authors.initials: MD
authors.lastname: Post
authors.forename: Kathryn B
authors.initials: KB
authors.lastname: Horwitz
authors.forename: Britta M
authors.initials: BM
authors.lastname: Jacobsen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D001952:Bridged-Ring Compounds / Q000494:pharmacology*; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects* / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D008870:Microtubules / Q000187:drug effects; D008938:Mitosis / Q000187:drug effects; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D043823:Taxoids / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D001952:Bridged-Ring Compounds; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D043823:Taxoids; C080625:taxane