Abstract 3453: CXCL10 contributes to aggressive disease progression in ING4-deficient breast cancer
Authors: Szeto Emily , Kim Suwon 
Published: August 2019

CXCL10 is a chemoattractant secreted by various cell types during inflammation for immune cells expressing its cognate receptor CXCR3. In breast cancer, CXCL10 has been associated with increased tumor lymphocytic infiltrates and poor patient prognosis. In addition, pharmacological inhibition of CXCR3 resulted in reduced lung metastases of mammary tumors in mice, suggesting CXCL10/CXCR3 signaling contributes to aggressive breast cancer. We previously identified CXCL10 as an NF-κB target gene repressed by Inhibitor of Growth 4 (ING4) in breast cancer cells. As ING4 deficiencies reported in 34% of breast tumors have been correlated with faster disease recurrence in patients, we investigated a functional interplay between CXCL10 and ING4. First, we assessed the clinical relevance of CXCL10, CXCR3, and/or ING4 expression levels using a public gene expression data set. Second, we genetically engineered T47D breast cancer cells to overexpress or delete the ING4 gene and determined cell phenotypes in the presence or absence of CXCL10 by utilizing cell migration assays and Western blot. Analysis of the GDS806 gene data set showed that patients with tumors expressing high levels of CXCL10 experienced significantly increased rates of disease recurrence while CXCR3 expression did not have a significant effect. The analysis also showed tumors expressing low levels of ING4 expressed higher levels of CXCL10, indicating an inverse expression pattern between the two genes. Moreover, patients with ING4-low/CXCL10-high tumors had a 4-fold faster recurrence rate compared to ING4-high/CXCL10-low tumor patients. These results indicated that high CXCL10 expression contributed to significantly accelerated disease recurrence compounded by low ING4 expression, suggesting a functional relationship between the two genes which may exacerbate tumor phenotypes. While CXCL10 did not affect growth rates of T47D cells with or without ING4, CXCL10 induced migration only in ING4-deleted cells. These results suggested that ING4 inhibited CXCL10 signaling. The western blot analyses showed no change in CXCR3 expression, but elevated phosphorylation of insulin-like growth factor 1 receptor (IGF1R) after CXCL10 treatment, suggesting CXCL10 may signal by activating IGF1R. Consistent with this idea, when cells were treated with an IGF1R inhibitor, Linsitinib (OSI-906), CXCL10-induced migration was attenuated in ING4-deleted cells. In conclusion, these results suggest that in order to promote an aggressive tumor phenotype, CXCL10 induces migration of ING4-deficient tumor cells in part by activating IGF1R. This study reports the first demonstration of the chemokine CXCL10 exerting a direct effect on breast cancer cells and puts forth the CXCL10/IGF1R signaling pathway as a potential therapeutic target for ING4-deficient aggressive breast cancer.

Citation Format: Emily Szeto, Suwon Kim. CXCL10 contributes to aggressive disease progression in ING4-deficient breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3453.