Institutional members access full text with Ovid®

Share this article on:

Induction of a menopausal state alters the growth and histology of ovarian tumors in a mouse model of ovarian cancer

Laviolette, Laura A. BSc1,2; Ethier, Jean-François PhD1,2; Senterman, Mary K. MD3; Devine, Patrick J. PhD4; Vanderhyden, Barbara C. PhD1,2

doi: 10.1097/gme.0b013e3181fca1b6
Original Articles

Objective: Ovarian cancer is often diagnosed in women after menopause when the levels of the serum gonadotropins follicle-stimulating hormone (FSH) and luteinizing hormone (LH) are increased because of the depletion of growing follicles within the ovary. The ability of FSH and LH to modulate the disease has not been well studied owing to a lack of physiologically relevant models of ovarian cancer. In this study, 4-vinylcyclohexene diepoxide (VCD) was used to deplete ovarian follicles and increase the levels of circulating FSH and LH in the tgCAG-LS-TAg mouse model of ovarian cancer.

Methods: VCD-induced follicle depletion was performed either before or after induction of the oncogene SV40 large and small T-antigens in the ovarian surface epithelial cells of tgCAG-LS-TAg mice, which was mediated by the intrabursal delivery of an adenovirus expressing Cre recombinase (AdCre).

Results: tgCAG-LS-TAg mice injected with AdCre developed undifferentiated ovarian tumors with mixed epithelial and stromal components and some features of sex cord stromal tumors. Treatment with VCD before or after AdCre injection yielded tumors of similar histology, but with the unique appearance of Sertoli cell nests. In mice treated with VCD before the induction of tumorigenesis, the ovarian tumors tended to grow more slowly. The human ovarian cancer cell lines SKOV3 and OVCAR3 responded similarly to increased levels of gonadotropins in a second model of menopause, growing more slowly in ovariectomized mice compared with cycling controls.

Conclusions: These results suggest that follicle depletion and increased gonadotropin levels can alter the histology and the rate of growth of ovarian tumors.

Received July 19, 2010; revised and accepted September 14, 2010.

From the 1Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada; 2Centre for Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada; 3Department of Pathology and Laboratory Medicine, The Ottawa Hospital, Ottawa, Ontario, Canada; and 4Institut National de la Recherche Scientifique (INRS)-Institut Armand Frappier, Laval, Quebec, Canada.

Funding/support: This work was supported by grants from the Ontario Institute for Cancer Research and the Canadian Institutes of Health Research (B.C.V.), a Scientific Scholar Award in Ovarian Cancer Research (sponsored by the Marsha Rivkin Centre for Ovarian Cancer Research, Seattle), and a Gynecological Cancer Research award from the Mitchell Family Fund, National Ovarian Cancer Association and Cancer Care Ontario (J-F.E.), and a doctoral research award from the Canadian Institutes of Health Research-Ontario Women's Health Council/Institute ofGender and Health (L.A.L). The University of Virginia Center for Research in Reproduction Ligand Assay and Analysis Core is supported bythe Eunice Kennedy Shriver National Institute of Child Health andHuman Development/National Institutes of Health (SCCPIR) grant U54-HD28934.

Financial disclosure/conflicts of interest: None reported.

Address correspondence to: Barbara C. Vanderhyden, PhD, Ottawa Hospital Research Institute, 501 Smyth Rd., Box 926, Ottawa, Ontario, Canada K1H 8L6. E-mail:

©2011The North American Menopause Society