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. © 2014 Chia et al.; licensee BioMed Central Ltd.