A matter of dosage: SF-1 in adrenocortical development and cancer.

Steroidogenic factor-1 (SF-1), a nuclear receptor transcription factor, has a pivotal role in adrenal and gonadal development in humans and mice. It was previously shown that Sf-1 dosage critically regulates adrenal size and function in mice, while in humans mutation of a single SF-1 allele leads to adrenal and/or gonadal dysgenesis. Recent studies have elucidated the role of an increased SF-1 dosage as an important pathogenetic factor in childhood adrenocortical cancer and in experimental adrenocortical cancer in mice and identified genes that are regulated by SF-1 in a dosage-dependent fashion. Drugs targeting SF-1 transcriptional activity may then represent potential therapeutic tools to be associated to current chemotherapeutic regimens for the treatment of adrenocortical cancer in children. The adrenal cortex is an essential component of the hypothalamic-pituitary-adrenal axis, synthesizing essential steroid hormones (mineralocorticoids, glucocorticoids and androgens) and regulating diverse biological processes, such as stress response, blood pressure, glucose metabolism and sexual development. The structure of the fetal adrenal cortex is unique in human and primates compared to other species. In fact, during intrauterine life, most of the inner part of the adrenal cortex (fetal zone) is occupied by large, steroid-secreting cells, which synthesize large amounts of dehydroepiandrosterone and its sulfate derivative (reviewed in [1]). Conversely, a few layers of cells lying in an outer, subcapsular position (definitive zone) are nonsteroidogenic and constitute a proliferative compartment in which most probably the precursors of fetal zone cells are generated. An additional zone (transitional zone) develops between the definitive and the fetal zone late in pregnancy and synthesizes cortisol. Steroid hormones produced by the fetal zone regulate intrauterine homeostasis, the maturation of the fetal organs necessary for