Over-Expression of Activin-β Is Associated with Murine and Human Prostate Disease.

Activins are members of the TGF-β superfamily and have been linked to prostate cancer. There are four mammalian activin subunits (β, β, β, and β) that dimerize to form functional proteins. The role of activin-A (β-β) has been relatively well characterized and has been shown to generally inhibit growth in the prostate. In contrast, little is known about the biological function of the β and β subunits. Previous work indicated activin-C (β-β) to be an antagonist of activin-A. This is important because resistance to activin-A growth inhibition occurs during prostate cancer progression. This paradox is not currently well understood. Hence, we hypothesize that local expression of the activin-β subunit antagonizes activin-A-dependent growth inhibition and represents a key factor contributing to acquired insensitivity to activin-A observed in prostate cancer progression. To test our hypothesis, we characterized the ventral prostate lobes of 9-month-old transgenic mice over-expressing activin-β and examined the expression of activin-β, activin-β, and the activin intracellular signaling factor, Smad-2, in human prostate diseases. Prostate epithelial cell hyperplasia, low-grade prostatic intraepithelial neoplasia (PIN) lesions, alterations in cell proliferation, and reduced Smad-2 nuclear localization were evident in mice over-expressing activin-β. Increased activin-β and -β subunit immunoreactive scores and decreased Smad-2 nuclear localization were also evident in human prostate cancer. This study suggests that over-expression of activin-β is associated with murine and human prostate pathologies. We conclude that the activin-β subunit may have therapeutic and/or diagnostic implications in human prostate disease.