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?-Adrenergic receptors suppress Rap1B prenylation and promote the metastatic phenotype in breast cancer cells.

ABSTRACT: A greater understanding of the molecular basis of breast cancer metastasis will lead to identification of novel therapeutic targets and better treatments. Rap1B is a small GTPase that suppresses the metastasis of breast cancer cells by increasing cell-cell adhesion. In breast cancer, a decrease in Rap1B prenylation and subsequent loss of Rap1B at the plasma membrane decreases cell-cell adhesion and increases cell scattering, which promotes the metastatic phenotype. Protein kinase A (PKA) was recently found to phosphorylate Rap1B and inhibit its prenylation. PKA is activated by G protein-coupled receptors (GPCR) that stimulate G?s. In this study, we investigated whether the general G?s activator, cholera toxin, and agonists of the ?-adrenergic receptor (?AR), which is a G?s-coupled GPCR, promote Rap1B phosphorylation and inhibit its prenylation. We show here that cholera toxin and ?AR activation phosphorylate Rap1B and inhibit its prenylation and membrane localization, reducing cell-cell adhesion and promoting cell scattering. Furthermore, we report that breast cancer cell migration is decreased by the FDA-approved ?-blocker, propranolol. Pharmacological targeting of GPCRs, especially those such as the ?AR that are regulated by FDA-approved drugs, to increase cell adhesion and decrease cell scattering could provide a promising therapeutic approach to reduce breast cancer metastasis.

SUBMITTER: Wilson JM

PROVIDER: S-EPMC4622671 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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β-Adrenergic receptors suppress Rap1B prenylation and promote the metastatic phenotype in breast cancer cells.

Wilson Jessica M JM Lorimer Ellen E Tyburski Michael D MD Williams Carol L CL

Cancer biology & therapy 20150724 9

A greater understanding of the molecular basis of breast cancer metastasis will lead to identification of novel therapeutic targets and better treatments. Rap1B is a small GTPase that suppresses the metastasis of breast cancer cells by increasing cell-cell adhesion. In breast cancer, a decrease in Rap1B prenylation and subsequent loss of Rap1B at the plasma membrane decreases cell-cell adhesion and increases cell scattering, which promotes the metastatic phenotype. Protein kinase A (PKA) was rec ...[more]

PMID: 26209110

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Project description:BackgroundDisseminated tumor cells (DTCs) in the bone marrow may exist in a dormant state for extended periods of time, maintaining the ability to proliferate upon activation, engraft at new sites, and form detectable metastases. However, understanding of the behavior and biology of dormant breast cancer cells in the bone marrow niche remains limited, as well as their potential involvement in tumor recurrence and metastasis. Therefore, the purpose of this study was to investigate the tumorigenicity and metastatic potential of dormant disseminated breast cancer cells (prior to activation) in the bone marrow.Methodology/principal findingsTotal bone marrow, isolated from mice previously injected with tumorspheres into the mammary fat pad, was injected into the mammary fat pad of NUDE mice. As a negative control, bone marrow isolated from non-injected mice was injected into the mammary fat pad of NUDE mice. The resultant tumors were analyzed by immunohistochemistry for expression of epithelial and mesenchymal markers. Mouse lungs, livers, and kidneys were analyzed by H+E staining to detect metastases. The injection of bone marrow isolated from mice previously injected with tumorspheres into the mammary fat pad, resulted in large tumor formation in the mammary fat pad 2 months post-injection. However, the injection of bone marrow isolated from non-injected mice did not result in tumor formation in the mammary fat pad. The DTC-derived tumors exhibited accelerated development of metastatic lesions within the lung, liver and kidney. The resultant tumors and the majority of metastatic lesions within the lung and liver exhibited a mesenchymal-like phenotype.Conclusions/significanceDormant DTCs within the bone marrow are highly malignant upon injection into the mammary fat pad, with the accelerated development of metastatic lesions within the lung, liver and kidney. These results suggest the acquisition of a more aggressive phenotype of DTCs during metastatic latency within the bone marrow microenvironment.

Dataset Information

?-Adrenergic receptors suppress Rap1B prenylation and promote the metastatic phenotype in breast cancer cells.

Publications

β-Adrenergic receptors suppress Rap1B prenylation and promote the metastatic phenotype in breast cancer cells.

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