دورية أكاديمية
PAQR8 promotes breast cancer recurrence and confers resistance to multiple therapies.
| العنوان: | PAQR8 promotes breast cancer recurrence and confers resistance to multiple therapies. |
|---|---|
| المؤلفون: | Chen S; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Room 614 BRB II/III, 421 Curie Boulevard, Philadelphia, PA, 19104-6160, USA.; Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA., Paul MR; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Room 614 BRB II/III, 421 Curie Boulevard, Philadelphia, PA, 19104-6160, USA.; 2-PREVENT Translational Center of Excellence, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.; Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA., Sterner CJ; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Room 614 BRB II/III, 421 Curie Boulevard, Philadelphia, PA, 19104-6160, USA.; 2-PREVENT Translational Center of Excellence, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.; Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA., Belka GK; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Room 614 BRB II/III, 421 Curie Boulevard, Philadelphia, PA, 19104-6160, USA.; 2-PREVENT Translational Center of Excellence, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.; Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA., Wang D; Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA., Xu P; Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA., Sreekumar A; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Room 614 BRB II/III, 421 Curie Boulevard, Philadelphia, PA, 19104-6160, USA.; Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA., Pan TC; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Room 614 BRB II/III, 421 Curie Boulevard, Philadelphia, PA, 19104-6160, USA.; 2-PREVENT Translational Center of Excellence, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.; Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA., Pant DK; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Room 614 BRB II/III, 421 Curie Boulevard, Philadelphia, PA, 19104-6160, USA.; 2-PREVENT Translational Center of Excellence, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.; Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA., Makhlin I; 2-PREVENT Translational Center of Excellence, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA., DeMichele A; 2-PREVENT Translational Center of Excellence, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA., Mesaros C; Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA., Chodosh LA; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Room 614 BRB II/III, 421 Curie Boulevard, Philadelphia, PA, 19104-6160, USA. chodosh@pennmedicine.upenn.edu.; 2-PREVENT Translational Center of Excellence, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. chodosh@pennmedicine.upenn.edu.; Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. chodosh@pennmedicine.upenn.edu.; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. chodosh@pennmedicine.upenn.edu. |
| المصدر: | Breast cancer research : BCR [Breast Cancer Res] 2023 Jan 03; Vol. 25 (1), pp. 1. Date of Electronic Publication: 2023 Jan 03. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S. |
| اللغة: | English |
| بيانات الدورية: | Publisher: BioMed Central Ltd Country of Publication: England NLM ID: 100927353 Publication Model: Electronic Cited Medium: Internet ISSN: 1465-542X (Electronic) Linking ISSN: 14655411 NLM ISO Abbreviation: Breast Cancer Res Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: London, UK : BioMed Central Ltd Original Publication: London, UK : Current Science, c1999- |
| مواضيع طبية MeSH: | Drug Resistance, Neoplasm*/genetics , Neoplasm Recurrence, Local*/genetics , Neoplasm Recurrence, Local*/pathology, Animals ; Mice ; Lapatinib ; Fulvestrant ; Receptor, ErbB-2/metabolism ; Estrogens ; Receptors, Progesterone |
| مستخلص: | Background: Breast cancer mortality is principally due to recurrent disease that becomes resistant to therapy. We recently identified copy number (CN) gain of the putative membrane progesterone receptor PAQR8 as one of four focal CN alterations that preferentially occurred in recurrent metastatic tumors compared to primary tumors in breast cancer patients. Whether PAQR8 plays a functional role in cancer is unknown. Notably, PAQR8 CN gain in recurrent tumors was mutually exclusive with activating ESR1 mutations in patients treated with anti-estrogen therapies and occurred in > 50% of both patients treated with anti-estrogen therapies and those treated with chemotherapy or anti-Her2 agents. Methods: We used orthotopic mouse models to determine whether PAQR8 overexpression or deletion alters breast cancer dormancy or recurrence following therapy. In vitro studies, including assays for colony formation, cell viability, and relative cell fitness, were employed to identify effects of PAQR8 in the context of therapy. Cell survival and proliferation were quantified by immunofluorescence staining for markers of apoptosis and proliferation. Sphingolipids were quantified by liquid chromatography-high resolution mass spectrometry. Results: We show that PAQR8 is necessary and sufficient for efficient mammary tumor recurrence in mice, spontaneously upregulated and CN gained in recurrent tumors that arise following therapy in multiple mouse models, and associated with poor survival following recurrence as well as poor overall survival in breast cancer patients. PAQR8 promoted resistance to therapy by enhancing tumor cell survival following estrogen receptor pathway inhibition by fulvestrant or estrogen deprivation, Her2 pathway blockade by lapatinib or Her2 downregulation, and treatment with chemotherapeutic agents. Pro-survival effects of PAQR8 were mediated by a G Conclusions: Our data provide in vivo evidence that PAQR8 plays a functional role in cancer, implicate PAQR8, cAMP, and ceramide metabolism in breast cancer recurrence, and identify a novel mechanism that may commonly contribute to the acquisition of treatment resistance in breast cancer patients. (© 2022. The Author(s).) |
| References: | Mol Pharmacol. 1999 May;55(5):787-94. (PMID: 10220556) Nature. 2012 Oct 4;490(7418):61-70. (PMID: 23000897) Cancer Res. 2013 Dec 1;73(23):6856-64. (PMID: 24217577) Nat Med. 2011 Jan;17(1):55-63. (PMID: 21186369) Bioinformatics. 2019 Aug 15;35(16):2847-2849. (PMID: 30596895) Breast Cancer Res. 2021 Jun 4;23(1):63. (PMID: 34088357) Mol Endocrinol. 2006 Jul;20(7):1519-34. (PMID: 16484338) Cell Metab. 2006 Dec;4(6):475-90. (PMID: 17141631) J Clin Invest. 2015 Jun;125(6):2484-96. (PMID: 25961456) Nature. 1993 Oct 7;365(6446):557-60. (PMID: 8413613) Nature. 1996 Jun 27;381(6585):800-3. (PMID: 8657285) Bioinformatics. 2009 Jul 15;25(14):1754-60. (PMID: 19451168) Cancer Cell. 2004 Dec;6(6):577-86. (PMID: 15607962) J Biol Chem. 1999 Jul 16;274(29):20296-300. (PMID: 10400650) Cancer Cell. 2016 Mar 14;29(3):255-269. (PMID: 26977878) Steroids. 2008 Oct;73(11):1160-73. (PMID: 18603275) Bioinformatics. 2014 Apr 1;30(7):923-30. (PMID: 24227677) Nucleic Acids Res. 2014 Dec 16;42(22):e168. (PMID: 25300484) Annu Rev Biochem. 2013;82:637-62. (PMID: 23527695) Cancer Cell. 2018 Sep 10;34(3):427-438.e6. (PMID: 30205045) N Engl J Med. 2016 Sep 22;375(12):1109-12. (PMID: 27653561) Cancer Res. 2014 Dec 15;74(24):7583-98. (PMID: 25239452) Nature. 2021 Aug;596(7873):590-596. (PMID: 34293799) Am J Physiol Cell Physiol. 2001 Dec;281(6):C2010-9. (PMID: 11698260) Bioanalysis. 2021 Jul;13(13):1037-1049. (PMID: 34110924) Cancer Discov. 2014 Jul;4(7):790-803. (PMID: 24786206) Proc Natl Acad Sci U S A. 1986 Apr;83(8):2496-500. (PMID: 3458212) Nature. 2017 Apr 6;544(7648):120-123. (PMID: 28329765) J Immunol. 1999 Feb 15;162(4):2049-56. (PMID: 9973477) Cancer Cell. 2002 Dec;2(6):451-61. (PMID: 12498714) FASEB J. 2002 Mar;16(3):283-92. (PMID: 11874978) Genome Biol. 2014;15(12):550. (PMID: 25516281) Nat Genet. 2013 Dec;45(12):1446-51. (PMID: 24185510) J Steroid Biochem Mol Biol. 2022 May;219:106082. (PMID: 35189329) CA Cancer J Clin. 2021 May;71(3):209-249. (PMID: 33538338) Sci Rep. 2017 Jul 12;7(1):5168. (PMID: 28701790) J Biol Chem. 2000 Jan 7;275(1):288-96. (PMID: 10617617) Nat Genet. 2013 Dec;45(12):1439-45. (PMID: 24185512) Mol Endocrinol. 2006 Dec;20(12):3146-64. (PMID: 16959873) Genome Res. 2014 Dec;24(12):2022-32. (PMID: 25236618) Nature. 2021 Aug;596(7873):583-589. (PMID: 34265844) Sci Rep. 2017 Dec 4;7(1):16878. (PMID: 29203879) Biochem J. 2000 Nov 15;352 Pt 1:135-43. (PMID: 11062066) Biochim Biophys Acta. 2002 Dec 30;1585(2-3):114-25. (PMID: 12531544) Anal Biochem. 1994 Dec;223(2):306-12. (PMID: 7887476) N Engl J Med. 2017 Nov 9;377(19):1836-1846. (PMID: 29117498) Proc Natl Acad Sci U S A. 2003 Mar 4;100(5):2237-42. (PMID: 12601167) Horm Cancer. 2010 Aug;1(4):167-76. (PMID: 21761364) NPJ Breast Cancer. 2017 Nov 17;3:45. (PMID: 29167821) Nat Med. 2001 Feb;7(2):235-9. (PMID: 11175856) Genes Dev. 2003 Feb 15;17(4):488-501. (PMID: 12600942) Proc Natl Acad Sci U S A. 2003 Mar 4;100(5):2231-6. (PMID: 12574519) J Steroid Biochem Mol Biol. 2010 Aug;121(3-5):611-8. (PMID: 20144714) Clin Cancer Res. 2014 Apr 1;20(7):1757-1767. (PMID: 24398047) J Clin Invest. 2020 Aug 3;130(8):4252-4265. (PMID: 32657779) J Recept Signal Transduct Res. 2009;29(1):67-73. (PMID: 19519172) PLoS One. 2012;7(10):e47995. (PMID: 23118918) Breast Cancer Res Treat. 2017 Aug;164(3):627-638. (PMID: 28500398) Bioinformatics. 2013 Jan 1;29(1):15-21. (PMID: 23104886) J Biol Chem. 1983 Apr 25;258(8):4870-5. (PMID: 6300102) Cell Death Differ. 2004 Dec;11(12):1287-98. (PMID: 15297884) Biochim Biophys Acta. 2002 Dec 30;1585(2-3):193-201. (PMID: 12531554) Steroids. 2007 Feb;72(2):111-6. (PMID: 17157338) Biochem Soc Trans. 2012 Feb;40(1):200-4. (PMID: 22260690) Mol Pharmacol. 2009 Apr;75(4):866-75. (PMID: 19066337) Endocrinology. 2009 Aug;150(8):3833-44. (PMID: 19423765) Cancer Cell. 2005 Sep;8(3):197-209. (PMID: 16169465) J Biol Chem. 1998 Nov 13;273(46):30419-26. (PMID: 9804808) J Endocrinol. 2006 Aug;190(2):247-60. (PMID: 16899559) J Exp Clin Cancer Res. 2014 Sep 02;33:70. (PMID: 25178656) Cancer Cell. 2013 Jul 8;24(1):30-44. (PMID: 23770012) |
| معلومات مُعتمدة: | R21 NS116315 United States NS NINDS NIH HHS; R21 NS116315 United States NH NIH HHS; R01 CA208273 United States NH NIH HHS; F30 CA253989 United States NH NIH HHS |
| فهرسة مساهمة: | Keywords: Breast cancer; Endocrine therapy; Translational research; Treatment resistance; Tumor recurrence |
| المشرفين على المادة: | 0VUA21238F (Lapatinib) 22X328QOC4 (Fulvestrant) EC 2.7.10.1 (Receptor, ErbB-2) 0 (Estrogens) 0 (Paqr8 protein, mouse) 0 (Receptors, Progesterone) |
| تواريخ الأحداث: | Date Created: 20230103 Date Completed: 20230105 Latest Revision: 20230228 |
| رمز التحديث: | 20231215 |
| مُعرف محوري في PubMed: | PMC9811758 |
| DOI: | 10.1186/s13058-022-01559-3 |
| PMID: | 36597146 |
| قاعدة البيانات: | MEDLINE |
Find this article in full text from Springer Verlag. 
Full Text Finder كن أول من يترك تعليقا!