Abstract
Runx1 participation in epithelial mammary cells is still under review. Emerging data indicates that Runx1 could be relevant for breast tumor promotion. However, to date no studies have specifically evaluated the functional contribution of Runx1 to control gene expression in mammary epithelial tumor cells. It has been described that Runx1 activity is defined by protein context interaction. Interestingly, Foxp3 is a breast tumor suppressor gene. Here we show that endogenous Runx1 and Foxp3 physically interact in normal mammary cells and this interaction blocks Runx1 transcriptional activity. Furthermore we demonstrate that Runx1 is able to bind to R-spondin 3 (RSPO3) and Gap Junction protein Alpha 1 (GJA1) promoters. This binding upregulates Rspo3 oncogene expression and downregulates GJA1 tumor suppressor gene expression in a Foxp3-dependent manner. Moreover, reduced Runx1 transcriptional activity decreases tumor cell migration properties. Collectively, these data provide evidence of a new mechanism for breast tumor gene expression regulation, in which Runx1 and Foxp3 physically interact to control mammary epithelial cell gene expression fate. Our work suggests for the first time that Runx1 could be involved in breast tumor progression depending on Foxp3 availability.
Highlights
The RUNX proteins belong to a family of transcription factors (RUNX1, 2 and 3) known to play crucial roles in hematopoiesis, osteogenesis and neurogenesis [1]
In this study we show for the first time that endogenous Runx1 and Foxp3 physically interact in mammary epithelial cells leading to the inhibition of Runx1 transcriptional activity
We demonstrate that Runx1 is able to actively promote oncogene Rspo3 and prevent Gap Junction protein Alpha 1 (GJA1) gene expression in mammary tumor cell lines
Summary
The RUNX proteins belong to a family of transcription factors (RUNX1, 2 and 3) known to play crucial roles in hematopoiesis, osteogenesis and neurogenesis [1]. RUNX1 activity has been comprehensively study in physiological and tumor contexts [2, 3]. It has a runt domain and is able to bind a common TG (T/C)GGT consensus binding site, inducing proliferation in a context-dependent manner [4,5,6]. In particular Runx has both transcriptional activation and inhibition domains that allow it to bind a plethora of co-factors, such as the tumor suppressor gene Foxp, which in turn modulates Runx1’s regulatory effect [7, 8]. Runx activity is still matter of debate and little is known about its direct role in breast cancer progression [9,10,11,12]. Ferrari and colleagues have shown using multivariate analysis that high expression of RUNX1 correlates with poor prognosis in triple negative human breast cancer and strongly suggest that Runx could be used as an independent prognostic marker in this subgroup of human breast cancer [13]
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