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Mouse Strain Susceptibility to Gonadectomy-Induced Adrenocortical Tumor Formation Correlates with the Expression of GATA-4 and Luteinizing Hormone Receptor

Departments of Pediatrics (M.B., S.B.P.-T., E.G., L.J.M., M.H., D.B.W.) and Molecular Biology and Pharmacology (L.J.M., D.B.W.), Washington University School of Medicine, St. Louis Children’s Hospital, St. Louis, Missouri 63110; Children’s Hospital, Program for Developmental and Reproductive Biology, Biomedicum Helsinki, University of Helsinki (H.P., S.K., M.H.), 00290 Helsinki, Finland; and Department of Physiology, Institute of Biomedicine, University of Turku (N.R., I.T.H.), 20520 Turku, Finland

Address all correspondence and requests for reprints to: David B. Wilson, M.D., Ph.D., Department of Pediatrics, Box 8208, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, Missouri 63110. E-mail: wilson_d{at}pcfnotes1.wustl.edu.

Certain inbred strains of mice, including DBA/2J, develop adrenocortical tumors in response to gonadectomy. Spindle-shaped cells with limited steroidogenic capacity, termed A cells, appear in the subcapsular region of the adrenal gland, followed by sex steroid-producing cells known as B cells. These changes result from unopposed gonadotropin production by the pituitary, but the adrenocortical factors involved in tumorigenesis have not been characterized. GATA-4, a transcription factor normally expressed in fetal, but not adult, adrenocortical cells, was found in neoplastic cells that proliferate in the adrenal cortex of gonadectomized DBA/2J mice. GATA-4 mRNA was detected in the adrenal glands of female mice 0.5 months after ovariectomy and reached a maximum by 4 months. Castrated male mice developed adrenocortical tumors more slowly than gonadectomized females, and the onset of GATA-4 expression in the adrenal was delayed. In situ hybridization and immunohistochemistry revealed GATA-4 mRNA and protein in A and B cells, but not in normal adrenocortical cells. mRNA encoding another factor associated with adrenocortical tumorigenesis, LH receptor (LHR), was detected in A and B cells. In addition, transcripts for P450 17-hydroxylase/C17-C20 lyase, an enzyme essential for the production of sex steroids, and inhibin- were found in B cells. Unilateral ovarian regeneration, a phenomenon known to occur in gonadectomized mice, was observed in a subset of DBA/2J mice undergoing complete ovariectomy. In these animals, adrenocortical tumor progression was arrested; A cells and GATA-4 expression were evident, but there was no expression of LHR or P450 17-hydroxylase/C17-C20 lyase. Strain susceptibility to adrenocortical tumorigenesis (DBA/2J >> FVB/N) correlated with the expression of GATA-4 and LHR, implicating these factors in the process of adrenocortical neoplasia in response to continuous gonadotropin stimulation.

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