Abstract
Dysregulated JAK/STAT signaling has been implicated in breast cancer metastasis, which is associated with high relapse risks. However, mechanisms underlying JAK/STAT signaling-mediated breast tumorigenesis are poorly understood. Here, we showed that GRAMD1B expression is upregulated on IL-6 but downregulated upon treatment with the JAK2 inhibitor AG490 in the breast cancer MDA-MB-231 cells. Notably, Gramd1b knockdown caused morphological changes of the cells, characterized by the formation of membrane ruffling and protrusions, implicating its role in cell migration. Consistently, GRAMD1B inhibition significantly enhanced cell migration, with an increase in the levels of the Rho family of GTPases. We also found that Gramd1b knockdown-mediated pro-migratory phenotype is associated with JAK2/STAT3 and Akt activation, and that JAK2 or Akt inhibition efficiently suppresses the phenotype. Interestingly, AG490 dose-dependently increased p-Akt levels, and our epistasis analysis suggested that the effect of JAK/STAT inhibition on p-Akt is via the regulation of GRAMD1B expression. Taken together, our results suggest that GRAMD1B is a key signaling molecule that functions to inhibit cell migration in breast cancer by negating both JAK/STAT and Akt signaling, providing the foundation for its development as a novel biomarker in breast cancer.
Highlights
Breast cancer is a clinically heterogeneous disease and has been ranked as the most common malignancy in women worldwide, with incidence rates high in developed countries and relative mortality rates greatest in less developed countries[1,2]
GRAMD1B expression is regulated by JAK/STAT signaling in the breast cancer MDA-MB-231 cells
Since the Drosophila ortholog of GRAMD1B was initially identified as a signaling component of the Drosophila JAK/ STAT pathway[17], we determined whether GRAMD1B expression is modulated by JAK/STAT signaling in the breast cancer MDA-MB-231 cells
Summary
Breast cancer is a clinically heterogeneous disease and has been ranked as the most common malignancy in women worldwide, with incidence rates high in developed countries and relative mortality rates greatest in less developed countries[1,2]. Immunohistochemical analyses with human breast tumor samples further revealed an increased level of IL-6 at the leading edge of invasive breast tumors, with its level positively correlated with advanced stage, confirming a pivotal role of IL-6 signaling in breast tumor metastasis in vivo[8]. Another signaling pathway commonly dysregulated in breast cancer is the PI3K/Akt signaling cascade[9,10]. Several studies have reported a cross-talk between PI3K/Akt and JAK/STAT signaling in metastatic breast tumors[4,16]. Our epistasis analysis suggested a central role of GRAMD1B in the linkage between JAK/STAT and Akt signaling
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