The role of luteinizing hormone (LH) and its receptor (LHCGR) signaling in the adrenal gland remains unknown. Gonadectomy-induced chronically elevated LH levels trigger neoplastic transformation in genetically susceptible mouse strains (DBA/2J) or transgenic mice expressing the Simian Virus 40 T antigen (SV40Tag) oncogene under inhibin-α promoter (inhα/Tag). In order to study the functional role of LHR and GATA4 in the onset and progression of adrenocortical tumors in ovariectomized (OVX) inhα/Tag females in vivo and in vitro, we crossbred the inhα/Tag with LHR knockout (LuRKO) mice. Additionally we knocked out Lhr (Lgrko) and Gata4 (Gata4-ko) in the Cα1 cell line derived from an adrenal tumor of inhα/Tag mice. In inhα/Tag mice, we identified two distinct types of SV40Tag expressing neoplastic cells. The first type, subcapsular non-steroidogenic spindle-shaped A-like cells, which never developed to tumors, were found in both intact and OVX inhα/Tag females. The second type, parenchymal tumor cells in the topmost layer of zona fasciculata, later forming tumor foci, were found only in OVX inhα/Tag mice. Lack of LHR in OVX inhα/Tag/LuRKO mice adrenals prevented tumor formation. Histological and immunohistochemical analyses revealed the presence of hyperplastic cells expressing SV40Tag in parenchyma. These cells were devoid of GATA4 and showed signs of apoptosis. In vitro, a complete inactivation of Gata4 significantly decreased cell proliferation, expression of tumor markers (Inha, SV40Tag, Lhcgr and Esr1) and gonadal-like steroidogenic phenotype of Cα1 cells. Our results suggest that at first, the tumor formation was LH-dependent, but later on became LH-independent. GATA4 is responsible for the Inha/SV40Tag expression, gonadal steroidogenic phenotype and possibly pro-survival pathways. Identifying GATA4 downstream targets in the adrenocortical tumors in both, inhα/Tag and human could be of importance to find potential therapeutic targets for human adrenocortical tumors.
20 - 23 May 2017
European Society of Endocrinology