NuclearReceptors2018 Invited Speaker (1) (14 abstracts)
Progesterone receptor regulation of breast cancer cell translation
Jessica Finlay-Schultz 1 , Austin E Gillen 2 , Heather M Brechbuhl 3 , Shawna B Matthews 1 , Britta M Jacobsen 1 , David L Bentley 2, , Peter Kabos 3 & Carol A Sartorius 1
1Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA; 2RNA Biosciences Initiative, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA; 3Department of Medicine, Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA; 4Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
Progesterone receptors (PR) are long recognized to suppress estrogen receptor (ER) mediated transcription in breast cancers. However, a mechanistic basis for this repression has been lacking. Recent reports indicate this occurs, in part, through global repositioning of ER on chromatin in the presence of selective PR modulators (SPRMS), both agonists and antagonists [1, 2]. The goal of our studies was to further understand the mechanisms by which PR impacts estrogen-dependent growth in solid tumor models chronically treated with SPRMs. We grew ER+PR+ breast cancer patient-derived xenografts (PDX) in the presence of E2 alone or E2 plus the natural hormone progesterone (P4) or a synthetic SPRM medroxyprogesterone acetate (MPA) and demonstrated the SPRMs suppress tumor growth similar to tamoxifen. In these tumors P4 and MPA alter up to half of ER regulated genes at the transcript level. However, the majority of these genes (>80%) either show no change in ER chromatin binding by ChIP-seq or have no ER binding sites near their promoter (±2 kb). We made the interesting discovery via PR ChIP-seq that PR (but not ER) is localized at a large fraction of RNA polymerase III (Pol III) regulated tRNA genes. RIME for PR and subsequent IP found that PR associates with the Pol III complex. Furthermore, select pre-tRNA transcripts and mature tRNA pools are decreased in SPRM treated tumors [3]. We therefore speculate that PR may indirectly impede ER action through regulation of translation. This could occur by reducing the overall bioavailability of tRNAs to reduce protein synthesis rates and curtail tumor growth. Furthermore, PR could alter the tRNA pool to selectively change translational preference through non-optimal codon usage, an increasingly recognized mechanism of cancer cell regulation. Studies are underway to test these hypotheses.
DOI: 10.1530/endoabs.54.IS9
Article tools
My recent searches
My recently viewed abstracts
Authors
Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
© Bioscientifica 2024 |
Privacy policy |
Cookie settings
BiosciAbstracts
Bioscientifica Abstracts is the gateway to a series of products that provide a permanent, citable record of abstracts for biomedical and life science conferences.
Find out more