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.
Highlights
The Runt-related transcription factor Runt-related transcription factor-2 (Runx2) is critical for skeletal development but is aberrantly expressed in breast cancers, and promotes cell growth and invasion
Runx2-depleted MDA-MB-231 and SUM-159-PT cells show increased apoptotic cell death with glucose- and serum-deprivation The invasive breast cancer cell lines and clinical specimens express high levels of Runx2 compared to nontumorigenic breast epithelial MCF-10A cells (Additional file 1: Figures S1A, S1B, Additional file 2: Figure S2 and [5,6,15])
These results suggest that Runx2 expression in invasive MDA-MB-231 and SUM-159-PT breast cancer cells protects from growth factor- and glucose starvation-induced cell death
Summary
The Runt-related transcription factor Runx is critical for skeletal development but is 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; the mechanisms underlying Runx role in survival of invasive breast cancer cells are still unclear. One signaling mechanism that regulates breast cancer cell survival and is widely used to develop drug targets is the phosphatidyl inositol 3′ kinase (PI3K)-Akt pathway [2]. The Runt-related transcription factor, Runx, is a key regulator of normal bone development, homeostasis and remodeling [4]; Runx is aberrantly expressed in several cancer types, including breast [5,6], prostate [7], lung [8], ovarian [9] and osteosarcoma [10,11]. The interaction of C-terminal domain of Runx with co-activators or co-repressors modulates downstream gene transcription in a contextdependent manner [13]
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