title: Over-Expression of Activin-βCIs 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 (βA, βB, βC, and βE) that dimerize to form functional proteins. The role of activin-A (βA-βA) 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 βCand βEsubunits. Previous work indicated activin-C (βC-βC) 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-βCsubunit 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-βCand examined the expression of activin-βA, activin-βC, 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-βC. Increased activin-βAand -βCsubunit immunoreactive scores and decreased Smad-2 nuclear localization were also evident in human prostate cancer. This study suggests that over-expression of activin-βCis associated with murine and human prostate pathologies. We conclude that the activin-βCsubunit may have therapeutic and/or diagnostic implications in human prostate disease.
authors.affiliation: Department of Anatomy, University of Otago, PO Box 913, Dunedin, 9054, New Zealand.
authors.forename: Edward C
authors.initials: EC
authors.lastname: Ottley
authors.affiliation: Department of Anatomy, University of Otago, PO Box 913, Dunedin, 9054, New Zealand. karen.reader@otago.ac.nz.
authors.forename: Karen L
authors.initials: KL
authors.lastname: Reader
authors.affiliation: Department of Anatomy, University of Otago, PO Box 913, Dunedin, 9054, New Zealand.
authors.forename: Kailun
authors.initials: K
authors.lastname: Lee
authors.affiliation: Department of Anatomy, University of Otago, PO Box 913, Dunedin, 9054, New Zealand.
authors.forename: Francesco E
authors.initials: FE
authors.lastname: Marino
authors.affiliation: Department of Anatomy, University of Otago, PO Box 913, Dunedin, 9054, New Zealand.
authors.forename: Helen D
authors.initials: HD
authors.lastname: Nicholson
authors.affiliation: Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC, Australia.
authors.forename: Gail P
authors.initials: GP
authors.lastname: Risbridger
authors.affiliation: Department of Anatomy, University of Otago, PO Box 913, Dunedin, 9054, New Zealand.
authors.forename: Elspeth
authors.initials: E
authors.lastname: Gold
mesh_terms: D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D028322:Inhibin-beta Subunits / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009367:Neoplasm Staging; D009374:Neoplasms, Experimental; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism*; D046888:Tissue Array Analysis / Q000379:methods; D015854:Up-Regulation
chemical_list: C504186:INHBC protein, human; D051899:Smad2 Protein; C103008:inhibin beta A subunit; D028322:Inhibin-beta Subunits