ORIGINAL RESEARCH The inhibin/activin signalling pathway in human gonadal and adrenal cancers

abstract: The biological function of the inhibin-a subunit (INHA) in gonadal tumorigenesis is different in humans compared with mouse. The INHA subunit is up-regulated in most human ovarian and testicular cancers but knock-out studies in mice showed the INHA subunit is a tumour suppressorwith gonadal andadrenal specificity.The INHAsubunit is a componentof the inhibin/activin signalling pathway,which includes activin receptors ActRIIA/IIB and intracellular Smads-2/3. To resolve the incongruity in function in humans versus mouse, we re-evaluated the inhibin/activin pathway in humangonadal and adrenal cancers using contemporary protein andmRNAexpressiondata formultiple pathway com-ponents rather than INHA alone.Weused an INHAantibody raised against theN-terminal domain to compare immunoreactivity with themore commonly used antibody raised against the C-terminal domain. This study also described, for the first time, a comprehensive protein expression profileof activin-bC in reproductiveand adrenal cancers, and its effect onahumangranulosa cell line, providing evidence for a role inovarian, testis and adrenal tumour biology.Ourdata show reduced INHAexpression at both protein andmRNA levels, and increased activin signalling in human testicular, ovarian andmalignant versus benign forms of adrenal cancer.We also found that activin-C acts as an activin-A antagonist by binding to activin receptor subunits IIA and IIB and modulating the canonical Smad pathway. In conclusion, analysis of the inhibin/activin signalling pathway helps to explain discrepancies arising from studies of only one hormone or subunit and suggests that altered expression of the inhibin and activin subunits is associated with reproductive and adrenal cancer biology