Novel markers of gonadectomy-induced adrenocortical neoplasia in the mouse and ferret

• Spinlw1, Insl3, & Foxl2 are upregulated in murine post-GDX adrenocortical tumors.
• FOXL2 immunoreactivity is evident in adrenocortical tumors from gonadectomized ferrets.
• Igfbp6 and Foxs1 are hypomethylated and upregulated in murine post-GDX adrenocortical tumors.
• Post-GDX adrenocortical tumors exhibit properties of female and male gonadal cells.

Gonadectomy (GDX) induces sex steroid-producing adrenocortical tumors in certain mouse strains and in the domestic ferret. Transcriptome analysis and DNA methylation mapping were used to identify novel genetic and epigenetic markers of GDX-induced adrenocortical neoplasia in female DBA/2J mice. Markers were validated using a combination of laser capture microdissection, quantitative RT-PCR, in situ hybridization, and immunohistochemistry. Microarray expression profiling of whole adrenal mRNA from ovariectomized vs. intact mice demonstrated selective upregulation of gonadal-like genes including Spinlw1 and Insl3 in GDX-induced adrenocortical tumors of the mouse. A complementary candidate gene approach identified Foxl2 as another gonadal-like marker expressed in GDX-induced neoplasms of the mouse and ferret. That both “male-specific” (Spinlw1) and “female-specific” (Foxl2) markers were identified is noteworthy and implies that the neoplasms exhibit mixed characteristics of male and female gonadal somatic cells. Genome-wide methylation analysis showed that two genes with hypomethylated promoters, Igfbp6 and Foxs1, are upregulated in GDX-induced adrenocortical neoplasms. These new genetic and epigenetic markers may prove useful for studies of steroidogenic cell development and for diagnostic testing.

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