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Breast cancer cell invasion mediated by G?12 signaling involves expression of interleukins-6 and -8, and matrix metalloproteinase-2.

ABSTRACT:

Background

Recent studies on the involvement of the G12 family of heterotrimeric G proteins (G?12 and G?13, the products of the GNA12 and GNA13 genes, respectively) in oncogenic pathways have uncovered a link between G12 signaling and cancer progression. However, despite a well characterized role of Rho GTPases, the potential role of secreted factors in the capacity of G12 signaling to promote invasion of cancer cells is just beginning to be addressed.

Methods

MDA-MB-231 and MCF10A breast cancer cell lines were employed as a model system to explore the involvement of secreted factors in G12-stimulated cell invasion. Factors secreted by cells expressing dominant-active G?12 were identified by protein array, and their involvement in breast cancer cell invasion was assessed through both RNAi-mediated knockdown and antibody neutralization approaches. Bioinformatics analysis of the promoter elements of the identified factors suggested NF-?B elements played a role in their enhanced expression, which was tested by chromatin immunoprecipitation.

Results

We found that signaling through the G?12 in MDA-MB-231 and MCF10A breast cancer cell lines enhances expression of interleukins (IL)-6 and -8, and matrix metalloproteinase (MMP)-2, and that these secreted factors play a role in G12-stimulated cell invasion. Furthermore, the enhanced expression of these secreted factors was found to be facilitated by the activation of their corresponding promoters, where NF-?B seems to be one of the major regulators. Inhibition of IL-6 and IL-8, or MMP-2 activity significantly decreased G?12-mediated cell invasion.

Conclusions

These studies confirm and extend findings that secreted factors contribute to the oncogenic potential of G12 signaling, and suggest potential therapeutic targets to control this process.

SUBMITTER: Chia CY

PROVIDER: S-EPMC4074425 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Publications

Breast cancer cell invasion mediated by Gα12 signaling involves expression of interleukins-6 and -8, and matrix metalloproteinase-2.

Chia Crystal Y CY Kumari Udhaya U Casey Patrick J PJ

Journal of molecular signaling 20140617

<h4>Background</h4>Recent studies on the involvement of the G12 family of heterotrimeric G proteins (Gα12 and Gα13, the products of the GNA12 and GNA13 genes, respectively) in oncogenic pathways have uncovered a link between G12 signaling and cancer progression. However, despite a well characterized role of Rho GTPases, the potential role of secreted factors in the capacity of G12 signaling to promote invasion of cancer cells is just beginning to be addressed.<h4>Methods</h4>MDA-MB-231 and MCF10 ...[more]

PMID: 24976858

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