ECE2014 Poster Presentations Endocrine tumours and neoplasia (99 abstracts)
Molecular mechanisms of unexpected promoting effects of progesterone and mifepristone on granulosa cell tumorigenesis
Donata Ponikwicka-Tyszko 1 , Marcin Chrusciel 1, , Joanna Stelmaszewska 3 , Piotr Bernaczyk 4 , Xiangdong Li 5 , Ilpo Huhtaniemi 2, , Slawomir Wolczynski 1, & Nafis A Rahman 2,
1Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Olsztyn, Poland; 2Department of Physiology, Institute of Biomedicine, University of Turku, Turku, Finland; 3Department of Reproduction and Gynecological Endocrinology, Medical University of Bialystok, Bialystok, Poland; 4Department of Medical Pathology, Medical University of Bialystok, Bialystok, Poland; 5State Key Lab for Agro-Biotechnology, China Agriculture University, Beijing, China; 6Institute of Reproductive and Developmental Biology (IRDB), Imperial College London, London, UK.
Antiprogestine mifepristone (MF) has been shown to inhibit ovarian epithelial cancer (OEC) cell growth in vitro and in vivo. Recent clinical trials with MF for human OEC were unsuccessful, for unknown reasons. Progesterone (P4) is believed to have preventive measures towards breast, endometrial or hOEC cancers. Hereby we analyzed the effects of P4 and MF on ovarian granulosa cell tumorigenesis (GCT) in vitro and in vivo, and characterized their progesterone receptors (PGR): nuclear PGA and PGRB, membrane (mPRα, mPRβ, mPRγ) and membrane components PGRMC1 and PGRMC2. A supra-physiological dose of P4 and MF, up to 5 μM, unexpectedly significantly stimulated cell proliferation in murine (KK-1 and NT-1) and human (KGN) GCT cell lines compared to non-stimulated group. Similarly, 1-month treatments of P4 and MF in vivo (vs non treated tumor/control) also stimulated granulosa cell tumor progression in GCT transgenic mice expressing Simian Virus 40 T antigen under inhibin-α promoter (Inhα/Tag). The Inhα/Tag mice, harboring GCT by 5-month of age with 100% penetrance, expressed all PGR types. Non-treated Inhα/Tag GCT showed high cellular atypia, multinuclear and bizzare cells, cysts surrounded by connective tissues with hyperplastic and tumorigenic cell populations. P4 and MF increased the Ki67 positive cells to 80-90 vs 60% in non-treated group. MF or P4 treatments upregulated TGFβ1, TGFβRI, TGFβRII, TGFβRIII and SMAD3 expression of the GCTs. TGFβRII was non-detectable in control non-treated group ovaries indicating an impaired/disrupted anti-cancer action of TGFβ in the Inhα/Tag GCTs. Taken together, our results suggest that MF or P4 treatments may induce TGFβRII in Inhα/Tag GCT and probably switch TGFβ function from tumor suppressive to pro-tumorigenic. In Inhα/Tag GCT, MF may act as selective PGR modulator agonist and be involved in tumor GCT progression by TGFβ1, TGFβRI, TGFβRII and SMAD3 pathway activation.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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