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Granulosa Cell-Specific Brca1 Loss Alone or Combined with Trp53 Haploinsufficiency and Transgenic FSH Expression Fails to Induce Ovarian Tumors
- Source :
- Hormones and Cancer. 6:142-152
- Publication Year :
- 2015
- Publisher :
- Springer Science and Business Media LLC, 2015.
-
Abstract
- 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.
- Subjects :
- 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
Subjects
Details
- ISSN :
- 18688500 and 18688497
- Volume :
- 6
- Database :
- OpenAIRE
- Journal :
- Hormones and Cancer
- Accession number :
- edsair.doi.dedup.....bf8292cee6d313f0ecee4a57ba7c34fe