The influence of growth hormone/insulin-like growth factor deficiency on prostatic dysplasia in pbARR2-Cre, PTEN knockout mice

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Abstract

BACKGROUND:

Elevated insulin-like growth factor-I (IGF-I) serum levels and phosphatase and tensin homolog (PTEN) loss are prostate cancer (PCa) risk factors that enhance androgen-responsive and castration-resistant PCa xenografts growth.

METHODS:

The impact of suppressed growth hormone (GH)/IGF-I levels on neoplastic initiation of PTEN-deficient prostate epithelia was assessed histologically and by epithelial-to-mesenchymal marker expression in Ghrhr D60G homozygous (lit/lit) and heterozygous (lit/+) pbARR2-Cre, PTEN(fl/fl) (PTEN -/-) mice. How suppressed GH/IGF-I levels impacted growth of PTEN -/- mouse-derived prostate cells (MPPK) was examined by growth and survival signaling of cells cultured in lit/+ or lit/lit serum.

RESULTS:

Body weight, prostate weight and serum GH and IGF-I levels were reduced in lit/lit relative to lit/+ PTEN -/- littermates. While the anterior lobes of lit/+ PTEN -/- prostates consistently presented swollen, indicative of ductal blockage, the degree of prostatic dysplasia in 15- and 20-week-old lit/lit and lit/+ PTEN -/- mice was indistinguishable as measured by normalized prostatic weight, tissue histology, or probasin, PSP94, E-cadherin, N-cadherin and vimentin expression. However, growth and AKT activation of MPPK cells was decreased when cultured in lit/lit serum as compared with lit/+ serum and restored in lit/lit serum supplemented with IGF-I and, to a lesser extent, GH.

CONCLUSIONS:

These results suggest that initiation of prostate carcinogenesis by loss of PTEN is not influenced by germline variation of genes encoding signaling molecules in the GH/IGF-I axis, but suggests that these factors may affect the progression of dysplastic phenotype and supports previous studies, indicating that the GH/IGF milieu does impact the growth of PTEN-deficient dysplastic prostatic cells once transformed.

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