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

Abstract

Activins are members of the TGF-β superfamily and have been linked to prostate cancer. There are four mammalian activin subunits (β_A, β_B, β_C, and β_E) that dimerize to form functional proteins. The role of activin-A (β_A-β_A) 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_C and β_E subunits. Previous work indicated activin-C (β_C-β_C) 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_C 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_C and examined the expression of activin-β_A, activin-β_C, 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_C. Increased activin-β_A and -β_C 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_C is associated with murine and human prostate pathologies. We conclude that the activin-β_C subunit may have therapeutic and/or diagnostic implications in human prostate disease.

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