Runx2 activates PI3K/Akt signaling via mTORC2 regulation in invasive breast cancer cells

Abstract

IntroductionThe Runt-related transcription factor Runx2 is critical for skeletal development but is also aberrantly expressed in breast cancers, and promotes cell growth and invasion. A de-regulated serine/threonine kinase Akt signaling pathway is implicated in mammary carcinogenesis and cell survival; however, the mechanisms underlying Runx2 role in survival of invasive breast cancer cells are still unclear.MethodsThe phenotypic analysis of Runx2 function in cell survival was performed by gene silencing and flow cytometric analysis in highly invasive MDA-MB-231 and SUM-159-PT mammary epithelial cell lines. The expression analysis of Runx2 and pAkt (serine 473) proteins in metastatic breast cancer specimens was performed by immunohistochemistry. The mRNA and protein levels of kinases and phosphatases functional in Akt signaling were determined by real-time PCR and Western blotting, while DNA-protein interaction was studied by chromatin immunoprecipitation assays.ResultsThe high Runx2 levels in invasive mammary epithelial cell lines promoted cell survival in Akt phosphorylation (pAkt-serine 473) dependent manner. The analysis of kinases and phosphatases associated with pAkt regulation revealed that Runx2 promotes pAkt levels via mammalian target of rapamycin complex-2 (mTORC2). The recruitment of Runx2 on mTOR promoter coupled with Runx2-dependent expression of mTORC2 component Rictor defined Runx2 function in pAkt-mediated survival of invasive breast cancer cells.ConclusionsOur results identified a novel mechanism of Runx2 regulatory crosstalk in Akt signaling that could have important consequences in targeting invasive breast cancer-associated cell survival.

O-GlcNAc Modification of the runt-Related Transcription Factor 2 (Runx2) Links Osteogenesis and Nutrient Metabolism in Bone Marrow Mesenchymal Stem Cells

“…Aberrant expression and activity of Runx proteins are implicated in leukemia, metastatic breast cancer, and defects in skeletal development and bone remodeling (2)(3)(4). Runx2 is expressed during early embryonic development in mesenchymal and cartilage condensations of the developing bone anlagen, and its transcription, activity, and stability are tightly regulated (5)(6)(7).…”

Histone Deacetylase Inhibitors Repress Tumoral Expression of the Proinvasive Factor RUNX2

“…Factors that are crucial during embryogenesis are often hijacked during cancer progression, and RUNX2 is not an exception. RUNX2 is increasingly recognized in cancer biology for its oncogenic properties and a large number of articles link the deregulation of RUNX2 expression with progression and metastasization of different types of epithelial tumors (1,(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). Regulation of RUNX2 may occur at multiple levels and through multiple signaling pathways.…”

Genome-Wide Transcriptome Analysis of Estrogen Receptor-Positive and Human Epithelial Growth Factor Receptor 2-Positive Breast Cancers by Ribonucleic Acid Sequencing

“…Similarly, PBX1 and RUNX2 have been indicated to be closely associated with other type of breast cancers [28, 29]. Specifically, PBX1 is a TALE homeodomain protein, and altered regulation of this gene was shown to play an essential role in the ER alpha-mediated transcriptional response driving aggressive tumors in breast cancers [28].…”

“…Specifically, PBX1 is a TALE homeodomain protein, and altered regulation of this gene was shown to play an essential role in the ER alpha-mediated transcriptional response driving aggressive tumors in breast cancers [28]. The aberrantly expressed Runt-related TF RUNX2 has been reported to promote cell growth and invasion via activating PI3K/Akt signaling in invasive breast cancer cells [29]. Another 2 TFs IKZF1 and NR1H4 predicted for binding enriched motifs were also demonstrated to possess oncogenic functions promoting cancer formation.…”