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The chemokine Cxcl10 has been associated with poor prognosis in breast cancer, but the mechanism is not well understood. Our previous study has shown that  CXCL10  was repressed by the ING4 tumor suppressor, suggesting a potential inverse functional relationship. We thus investigated a role for Cxcl10 in the context of ING4 deficiencies in breast cancer. We first analyzed public gene expression data sets and found that patients with  CXCL10 -high/ ING4 -low expressing tumors had significantly reduced disease-free survival in breast cancer.  In vitro , Cxcl10 induced migration of  ING4 -deleted breast cancer cells but not of  ING4 -intact cells. Using inhibitors, we found that Cxcl10-induced migration of  ING4 -deleted cells required Cxcr3, Egfr, and the G β γ subunits downstream of Cxcr3 but not G α i. Immunofluorescent imaging showed that Cxcl10 induced early transient colocalization between Cxcr3 and Egfr in both  ING4 -intact and  ING4 -deleted cells, which recurred only in  ING4 -deleted cells. A peptide agent that binds to the internal juxtamembrane domain of Egfr inhibited Cxcr3/Egfr colocalization and cell migration. Taken together, these results presented a novel mechanism of Cxcl10 that elicits migration of  ING4 -deleted cells, in part by inducing a physical or proximal association between Cxcr3 and Egfr and signaling downstream via G β γ. These results further indicated that ING4 plays a critical role in the regulation of Cxcl10 signaling that enables breast cancer progression.

Cxcl10 Chemokine Induces Migration of ING4-Deficient Breast Cancer Cells via a Novel Cross Talk Mechanism between the Cxcr3 and Egfr Receptors