Granulosa Cell-Specific Brca1 Loss Alone or Combined with Trp53 Haploinsufficiency and Transgenic FSH Expression Fails to Induce Ovarian Tumors
| Autor: | Reena Desai, Kirsty A Walters, David J. Handelsman, Charles M. Allan, Dannielle H. Upton, Emily K. Colvin, Emily S. Fuller, Mark Jimenez, Viive M. Howell |
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| Rok vydání: | 2015 |
| Předmět: |
endocrine system
Cancer Research medicine.medical_specialty endocrine system diseases Endocrinology Diabetes and Metabolism Transgene Granulosa cell Cystadenoma Mice Transgenic Ovary Haploinsufficiency Biology medicine.disease_cause Mice Endocrinology Internal medicine medicine Animals skin and connective tissue diseases Ovarian Neoplasms Estrous cycle Granulosa Cells Estradiol BRCA1 Protein Endocrine and Autonomic Systems Uterus medicine.disease medicine.anatomical_structure Oncology Female Follicle Stimulating Hormone Tumor Suppressor Protein p53 Ovarian cancer Carcinogenesis Hormone |
| Zdroj: | Hormones and Cancer. 6:142-152 |
| ISSN: | 1868-8500 1868-8497 |
| DOI: | 10.1007/s12672-015-0222-5 |
| Popis: | BRCA1 mutations are associated with ovarian cancer. Previous studies reported that murine granulosa cell (GC) Brca1 loss caused ovarian-uterine tumors resembling serous cystadenomas, but the pathogenesis of these tumors may have been confounded by ectopic Brca1 expression and altered estrous cycling. We have used Tg.AMH.Cre conferring proven ovarian and GC-specific Cre activity to selectively target Brca1 disruption, denoted Brca1 GC−/−. Furthermore, ovary-specific Brca1 GC−/− was combined with global Trp53 haploinsufficiency (Trp53 +/−) and transgenic follicle-stimulating hormone (Tg.FSH) overexpression as a multi-hit strategy to investigate additional genetic and hormonal ovarian tumorigenesis mechanisms. However, 12-month-old Brca1 GC−/− mice had no detectable ovarian or uterine tumors. Brca1 GC−/− mice had significantly increased ovary weights, follicles exhibiting more pyknotic granulosa cells, and fewer corpora lutea with regular estrous cycling compared to controls. Isolated Brca1 GC−/− mutation lengthened the estrous cycle and proestrus stage; however, ovarian cystadenomas were not observed, even when Brca1 GC−/− was combined with Trp53 +/− and overexpressed Tg.FSH. Our Brca1 GC−/− models reveal that specific intra-follicular Brca1 loss alone, or combined with cancer-promoting genetic (Trp53 loss) and endocrine (high serum FSH) changes, was not sufficient to cause ovarian tumors. Our findings show that the ovary is remarkably resistant to oncogenesis, and support the emerging view of an extragonadal, multi-hit origin for ovarian tumorigenesis. |
| Databáze: | OpenAIRE |
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