caa a22 4500 606236007 CHVBK 20210128101245.0 cr unu---uuuuu 210128e20151201xx s 000 0 eng 10.1007/s11010-015-2551-7 doi (NATIONALLICENCE)springer-10.1007/s11010-015-2551-7 The cholesterol metabolite 27-hydroxycholesterol regulates p53 activity and increases cell proliferation via MDM2 in breast cancer cells [Elektronische Daten] [Shaneabbas Raza, Joyce Ohm, Archana Dhasarathy, Jared Schommer, Conor Roche, Kimberly Hammer, Othman Ghribi] Estrogen is synthesized from cholesterol and high cholesterol levels are suggested to be associated with increased risk of estrogen receptor(ER)-positive breast cancer. The cholesterol metabolite 27-hydroxycholesterol (27-OHC) was recently identified as a selective estrogen receptor modulator (SERM) and may therefore impact breast cancer progression. However, the mechanisms by which 27-OHC may contribute to breast cancer are not all known. We determined the extent to which 27-OHC regulates cell proliferation in MCF7 ER-positive breast cancer cell line involving the tumor suppressor protein p53. We found that treatment of MCF7 cells with 27-OHC resulted reduced p53 transcriptional activity. Conversely, treatment of the ER-negative MDA-MB 231 cells with 27-OHC induced no significant change in p53 activity. Exposure of MCF7 cells to 27-OHC was also associated with increased protein levels of the E3 ubiquitin protein ligase MDM2 and decreased levels of p53. Moreover, 27-OHC also enhanced physical interaction between p53 and MDM2. Furthermore, 27-OHC-induced proliferation was attenuated using either the p53 activator Tenovin-1 or the MDM2 inhibitor Nutlin-3 and Mdm2 siRNA. Taken together, our results indicate that 27-OHC may contribute to ER-positive breast cancer progression by disrupting constitutive p53 signaling in an MDM2-dependent manner. Springer Science+Business Media New York, 2015 27-Hydroxycholesterol nationallicence Breast cancer nationallicence Proliferation nationallicence Estrogen nationallicence Cholesterol nationallicence Raza Shaneabbas Department of Basic Sciences, University of North Dakota School of Medicine and Health Sciences, 501 North Columbia Road, 58202, Grand Forks, ND, USA aut Ohm Joyce Department of Basic Sciences, University of North Dakota School of Medicine and Health Sciences, 501 North Columbia Road, 58202, Grand Forks, ND, USA aut Dhasarathy Archana Department of Basic Sciences, University of North Dakota School of Medicine and Health Sciences, 501 North Columbia Road, 58202, Grand Forks, ND, USA aut Schommer Jared Department of Basic Sciences, University of North Dakota School of Medicine and Health Sciences, 501 North Columbia Road, 58202, Grand Forks, ND, USA aut Roche Conor Department of Basic Sciences, University of North Dakota School of Medicine and Health Sciences, 501 North Columbia Road, 58202, Grand Forks, ND, USA aut Hammer Kimberly Department of Veteran Affairs, Fargo VA Health Care System, 58102, Fargo, ND, USA aut Ghribi Othman Department of Basic Sciences, University of North Dakota School of Medicine and Health Sciences, 501 North Columbia Road, 58202, Grand Forks, ND, USA aut Molecular and Cellular Biochemistry Springer US; http://www.springer-ny.com 410/1-2(2015-12-01), 187-195 0300-8177 410:1-2<187 2015 410 11010 https://doi.org/10.1007/s11010-015-2551-7 text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s11010-015-2551-7 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Raza Shaneabbas Department of Basic Sciences, University of North Dakota School of Medicine and Health Sciences, 501 North Columbia Road, 58202, Grand Forks, ND, USA aut NATIONALLICENCE 700 1- Ohm Joyce Department of Basic Sciences, University of North Dakota School of Medicine and Health Sciences, 501 North Columbia Road, 58202, Grand Forks, ND, USA aut NATIONALLICENCE 700 1- Dhasarathy Archana Department of Basic Sciences, University of North Dakota School of Medicine and Health Sciences, 501 North Columbia Road, 58202, Grand Forks, ND, USA aut NATIONALLICENCE 700 1- Schommer Jared Department of Basic Sciences, University of North Dakota School of Medicine and Health Sciences, 501 North Columbia Road, 58202, Grand Forks, ND, USA aut NATIONALLICENCE 700 1- Roche Conor Department of Basic Sciences, University of North Dakota School of Medicine and Health Sciences, 501 North Columbia Road, 58202, Grand Forks, ND, USA aut NATIONALLICENCE 700 1- Hammer Kimberly Department of Veteran Affairs, Fargo VA Health Care System, 58102, Fargo, ND, USA aut NATIONALLICENCE 700 1- Ghribi Othman Department of Basic Sciences, University of North Dakota School of Medicine and Health Sciences, 501 North Columbia Road, 58202, Grand Forks, ND, USA aut NATIONALLICENCE 773 0- Molecular and Cellular Biochemistry Springer US; http://www.springer-ny.com 410/1-2(2015-12-01), 187-195 0300-8177 410:1-2<187 2015 410 11010