Dataset Information

Elevated cyclic AMP levels promote BRAFCA/Pten-/- mouse melanoma growth but pCREB is negatively correlated with human melanoma progression.

ABSTRACT: Melanocyte development and differentiation are regulated by cAMP, which is produced by the adenylate cyclase (AC) enzyme upon activation of the melanocortin-1-receptor (MC1R). Individuals carrying single amino acid substitution variants of MC1R have impaired cAMP signaling and higher risk of melanoma. However, the contribution of AC to this risk is not clear. Downstream of AC, the phosphorylated transcription factor, cyclic AMP Responsive Element Binding Protein (pCREB), which is activated by protein kinase A, regulates the expression of several genes including the melanocyte master regulator MITF. The roles of AC and CREB in melanoma development and growth are not well understood. Here, we investigated the effect of topical application of AC inhibitor on BrafCA/Pten-/- mouse melanoma development. We show that AC inhibitor delays melanoma growth independent of MAPK pathway activity and melanin content. Next, employing a primary melanoma tissue microarray and quantitative immunohistochemistry, we show that pCREB levels are positively correlated with the proliferative status of melanoma, but low pCREB expression is associated with tumor aggressiveness and metastatic recurrence. These data suggest that low cAMP signaling inhibits tumor growth but is a predictor of melanoma aggressiveness.

SUBMITTER: Rodriguez CI

PROVIDER: S-EPMC5743623 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Elevated cyclic AMP levels promote BRAF<sup>CA</sup>/Pten<sup>-/-</sup> mouse melanoma growth but pCREB is negatively correlated with human melanoma progression.

Rodríguez Carlos I CI Castro-Pérez Edgardo E Longley B Jack BJ Setaluri Vijayasaradhi V

Cancer letters 20171124

Melanocyte development and differentiation are regulated by cAMP, which is produced by the adenylate cyclase (AC) enzyme upon activation of the melanocortin-1-receptor (MC1R). Individuals carrying single amino acid substitution variants of MC1R have impaired cAMP signaling and higher risk of melanoma. However, the contribution of AC to this risk is not clear. Downstream of AC, the phosphorylated transcription factor, cyclic AMP Responsive Element Binding Protein (pCREB), which is activated by pr ...[more]

PMID: 29179997

Similar Datasets

Project description:Parathyroid hormone-related protein (PTHrP) expression in breast cancer is enriched in bone metastases compared to primary tumors. Human MCF7 breast cancer cells "home" to the bones of immune deficient mice following intracardiac inoculation, but do not grow well and stain negatively for Ki67, thus serving as a model of breast cancer dormancy in vivo. We have previously shown that PTHrP overexpression in MCF7 cells overcomes this dormant phenotype, causing them to grow as osteolytic deposits, and that PTHrP-overexpressing MCF7 cells showed significantly lower expression of genes associated with dormancy compared to vector controls. Since early work showed a lack of cyclic AMP (cAMP) response to parathyroid hormone (PTH) in MCF7 cells, and cAMP is activated by PTH/PTHrP receptor (PTHR1) signaling, we hypothesized that the effects of PTHrP on dormancy in MCF7 cells occur through non-canonical (i.e., PTHR1/cAMP-independent) signaling. The data presented here demonstrate the lack of cAMP response in MCF7 cells to full length PTHrP(1-141) and PTH(1-34) in a wide range of doses, while maintaining a response to three known activators of adenylyl cyclase: calcitonin, prostaglandin E2 (PGE2), and forskolin. PTHR1 mRNA was detectable in MCF7 cells and was found in eight other human breast and murine mammary carcinoma cell lines. Although PTHrP overexpression in MCF7 cells changed expression levels of many genes, RNAseq analysis revealed that PTHR1 was unaltered, and only 2/32 previous PTHR1/cAMP responsive genes were significantly upregulated. Instead, PTHrP overexpression in MCF7 cells resulted in significant enrichment of the calcium signaling pathway. We conclude that PTHR1 in MCF7 breast cancer cells is not functionally linked to activation of the cAMP pathway. Gene expression responses to PTHrP overexpression must, therefore, result from autocrine or intracrine actions of PTHrP independent of PTHR1, through signals emanating from other domains within the PTHrP molecule.

Dataset Information

Elevated cyclic AMP levels promote BRAFCA/Pten-/- mouse melanoma growth but pCREB is negatively correlated with human melanoma progression.

Publications

Elevated cyclic AMP levels promote BRAF<sup>CA</sup>/Pten<sup>-/-</sup> mouse melanoma growth but pCREB is negatively correlated with human melanoma progression.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets