Progesterone (P4) treatment has been shown to have a clear modulating effect on murine Leydig tumor cell (mLTC-1) function, including downregulation of luteinizing hormone receptor. We hypothesized that P4 would stimulate, whereas an antiprogestine mifepristone (MF) block tumor progression in vivo in a transgenic (TG) murine Leydig cell tumor model (inhibin-α promoter-driven SV40 T-antigen (inhα/Tag)) and act similarly on cell proliferation in vitro. Supra-physiological doses, up to 5 μM, of P4 and unexpectedly MF significantly stimulated cell proliferation in murine BLT-1 and mLTC-1 cell lines compared to non-stimulated controls. Similarly, 1 month treatment of P4 and MF in vivo (vs non treated controls), starting at 5.5 month of age, stimulated the progression of discernible Leydig cell tumor in inhα/Tag mice. The TG tumors, as well as BLT-1 and mLTC-1 cell lines, expressed nuclear progesterone receptors (PR) A and B, membrane PRs α, β, and γ and membrane components PGRMC1 and PGRMC2. Non-treated Inhα/Tag testes histopathologically presented with severe cellular atypia, only few peripheral tubular structures with spermatogenic cells up to elongated spermatids and a rapid tumor growth, some parts with necrosis and/or hemosiderin. In the P4- and MF-treated groups, testicular histopathology showed overall destroyed cellular morphology with blood filled cavities, infiltrating lymphocytes, and large parts with Leydig cell tumors with almost none of the normal testicular structures left. MF or P4 treatments upregulated Tgfbr2 and Alk1 and promoted alternative TGFβ pathway activation in inhα/Tag Leydig cell tumors. Moreover, MF treatment downregulated Smad6 (inhibitor of ALK1 signaling) and upregulated Smad7, a blocker for SMAD2/SMAD3 complex; whereas P4 upregulated endoglin, co-receptor for TGFβ receptor complex. These findings provide novel mechanistic insights on selective PR modulator MF acting as P4 agonist and promoting Leydig cell tumorigenesis in inhα/Tag TG mice through pro-tumorigenic Tgfbr2 signaling pathway.
03 - 07 May 2014
European Society of Endocrinology