Mechanisms of tumorigenesis in the inhibin-null mouse: An analysis of dysregulated TGF-beta family signaling in steroidogenic organs.

The transforming growth factor-beta (TGFbeta) family of signaling ligands encompasses a group of highly conserved proteins that play critical roles in metazoan development and physiology. TGFbeta family ligands signal through a membrane complex composed of TypeI and TypeII receptors, which transduce intracellular signals via Smad proteins. Activated Smad proteins act as promoter-specific transcription factors to induce changes in cellular growth and differentiation. Inhibin is an atypical member of the TGFbeta family, which selectively inhibits signaling by other TGFbeta family members. Inhibin is classically understood to antagonize signaling by activin, a canonical TGFbeta ligand that signals through Smad2 and Smad3. Opposing interactions between inhibin and activin regulate the function of the hypothalamic-pituitary-gonadal (HPG) axis and steroidogenic cell proliferation in the gonads. Inhibin-null (Inha-/-) mice display defects in both processes, exhibiting elevated follicle stimulating hormone (FSH) levels and estrogen-secreting gonadal tumors. Inha-/- mice develop estrogen-secreting adrenocortical neoplasms upon surgical gonadectomy, indicating that inhibin also regulates adrenocortical cell growth. The work presented in this thesis has attempted to elucidate several aspects of gonadal and adrenal tumorigenesis in Inha-/- mice, including the cellular identity of these neoplasms and signaling mechanisms involved in tumorigenesis. My studies have revealed that the adrenocortical neoplasms in Inha-/- mice are derived from misspecified adrenocortical stem/progenitor cells, which undergo a change in cellular fate to form gonadal tumors in the adrenal. These tumors have similar steroidogenic and transcriptional profiles to Inha-/- gonadal tumors, suggesting that the tumor-suppressing mechanism of inhibin is conserved between the gonads and adrenal. This assertion is supported by the common dependence of both tumor types on Smad3, which is required for efficient tumor cell proliferation. Genetic removal of Smad3 from Inha-/- mice disrupts mitogenic signaling by both activin and follicle stimulating hormone, and dramatically attenuates disease progression in the adrenal and gonad. Despite this similarity, tumorigenesis in the Inha-/- adrenal cortex may also involve unique mechanisms independent of activin signaling. My studies particularly implicate a novel interaction between inhibin and TGFbeta2 in adrenocortical tumor initiation, suggesting that inhibin may play multiple complex roles in cell fate determination and cellular growth suppression in steroidogenic tissues.PhDBiological SciencesCellular biologyMolecular biologyPhysiologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/126224/2/3238023.pd