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Hormones and Cancer

, Volume 6, Issue 4, pp 142–152 | Cite as

Granulosa Cell-Specific Brca1 Loss Alone or Combined with Trp53 Haploinsufficiency and Transgenic FSH Expression Fails to Induce Ovarian Tumors

  • Dannielle H. Upton
  • Emily S. Fuller
  • Emily K. Colvin
  • Kirsty A. Walters
  • Mark Jimenez
  • Reena Desai
  • David J. Handelsman
  • Viive M. Howell
  • Charles M. AllanEmail author
Original Paper

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.

Keywords

Ovarian Cancer Granulosa Cell BRCA1 Mutation Corpus Luteum Estrous Cycle 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

We thank Mamdouh Khalil and the staff of the ANZAC and Kolling Institute animal facilities.

Conflict of Interest

The authors declare that they have no competing interests.

Funding

This work was supported by the National Health and Medical Research Council (Australia) Project Grant (APP1008160) (CMA, DJH, KAW, VMH), Cancer council NSW project grant (VMH), and Cancer Institute NSW Fellowship (VMH).

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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Dannielle H. Upton
    • 1
  • Emily S. Fuller
    • 2
  • Emily K. Colvin
    • 2
  • Kirsty A. Walters
    • 1
  • Mark Jimenez
    • 1
  • Reena Desai
    • 1
  • David J. Handelsman
    • 1
  • Viive M. Howell
    • 2
  • Charles M. Allan
    • 1
    Email author
  1. 1.ANZAC Research InstituteUniversity of Sydney, Concord HospitalSydneyAustralia
  2. 2.Kolling Institute of Medical ResearchUniversity of SydneySt. LeonardsAustralia

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