Evan Delgado1, Michelle M Boisen2, Robin Laskey3, Rui Chen4, Chi Song4, Jad Sallit5, Zachary A Yochum6, Courtney L Andersen7, Matthew J Sikora8, Jacob Wagner1, Stephen Safe9, Esther Elishaev10, Adrian Lee8, Robert P Edwards3, Paul Haluska11, George Tseng4, Mark Schurdak1, Steffi Oesterreich8. 1. University of Pittsburgh Drug Discovery Institute, Pittsburgh, PA, USA. 2. Division of Gynecologic Oncology, Magee-Womens Hospital of the University of Pittsburgh Medical Center, Pittsburgh, PA, USA. Electronic address: boockmeiermm@mail.magee.edu. 3. Division of Gynecologic Oncology, Magee-Womens Hospital of the University of Pittsburgh Medical Center, Pittsburgh, PA, USA. 4. Department of Biostatistics and Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA. 5. Ross University School of Medicine. 6. Department of Medicine, Division of Hematology Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA. 7. Department of Pharmacology and Chemical Biology, Womens Cancer Research Center, Magee-Womens Research Institute, and University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA; Molecular Pharmacology Training Program, University of Pittsburgh School of Medicine, Pittsburgh, PA. 8. Department of Pharmacology and Chemical Biology, Womens Cancer Research Center, Magee-Womens Research Institute, and University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA. 9. Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX, USA. 10. Department of Pathology, Magee-Womens Hospital of the University of Pittsburgh Medical Center, Pittsburgh, PA, USA. 11. Department of Oncology and Pharmacology, Mayo Clinic, Rochester, MN, USA.
Abstract
OBJECTIVE: Nuclear receptors (NRs) play a vital role in the development and progression of several cancers including breast and prostate. Using TCGA data, we sought to identify critical nuclear receptors in high grade serous ovarian cancers (HGSOC) and to confirm these findings using in vitro approaches. METHODS: In silico analysis of TCGA data was performed to identify relevant NRs in HGSOC. Ovarian cancer cell lines were screened for NR expression and functional studies were performed to determine the significance of these NRs in ovarian cancers. NR expression was analyzed in ovarian cancer tissue samples using immunohistochemistry to identify correlations with histology and stage of disease. RESULTS: The NR4A family of NRs was identified as a potential driver of ovarian cancer pathogenesis. Overexpression of NR4A1 in particular correlated with worse progression free survival. Endogenous expression of NR4A1 in normal ovarian samples was relatively high compared to that of other tissue types, suggesting a unique role for this orphan receptor in the ovary. Expression of NR4A1 in HGSOC cell lines as well as in patient samples was variable. NR4A1 primarily localized to the nucleus in normal ovarian tissue while co-localization within the cytoplasm and nucleus was noted in ovarian cancer cell lines and patient tissues. CONCLUSIONS: NR4A1 is highly expressed in a subset of HGSOC samples from patients that have a worse progression free survival. Studies to target NR4A1 for therapeutic intervention should include HGSOC.
OBJECTIVE: Nuclear receptors (NRs) play a vital role in the development and progression of several cancers including breast and prostate. Using TCGA data, we sought to identify critical nuclear receptors in high grade serous ovarian cancers (HGSOC) and to confirm these findings using in vitro approaches. METHODS: In silico analysis of TCGA data was performed to identify relevant NRs in HGSOC. Ovarian cancer cell lines were screened for NR expression and functional studies were performed to determine the significance of these NRs in ovarian cancers. NR expression was analyzed in ovarian cancer tissue samples using immunohistochemistry to identify correlations with histology and stage of disease. RESULTS: The NR4A family of NRs was identified as a potential driver of ovarian cancer pathogenesis. Overexpression of NR4A1 in particular correlated with worse progression free survival. Endogenous expression of NR4A1 in normal ovarian samples was relatively high compared to that of other tissue types, suggesting a unique role for this orphan receptor in the ovary. Expression of NR4A1 in HGSOC cell lines as well as in patient samples was variable. NR4A1 primarily localized to the nucleus in normal ovarian tissue while co-localization within the cytoplasm and nucleus was noted in ovarian cancer cell lines and patient tissues. CONCLUSIONS:NR4A1 is highly expressed in a subset of HGSOC samples from patients that have a worse progression free survival. Studies to target NR4A1 for therapeutic intervention should include HGSOC.
Authors: Y Pekarsky; C Hallas; A Palamarchuk; A Koval; F Bullrich; Y Hirata; R Bichi; J Letofsky; C M Croce Journal: Proc Natl Acad Sci U S A Date: 2001-03-27 Impact factor: 11.205