Chromatin, Gene, and RNA Regulation mda-7/IL-24 Expression Inhibits Breast Cancer through Upregulation of Growth Arrest-Specific Gene 3 (gas3) and Disruption of b1 Integrin Function

Melanoma differentiation-associated gene (MDA)-7)/interleukin (IL)-24, a member of the IL-10 family of cytokines, inhibits growth of various human cancer cells, yet the underlying mechanism is largely unknown. Here, we report that mda-7/IL-24 efficiently suppresses the development of rat mammary tumors in vivo. Microarray analysis for genes differentially expressed in rat mammary tumor cells overexpressingMDA-7/IL-24 compared with those that do not express this cytokine identified growth arrest-specific gene-3 (gas3) as a target for mda-7/IL-24. Upregulation of gas3 by mda-7/IL-24 was STAT3 dependent. Induction of gas3 inhibited attachment and proliferation of tumor cells in vitro and in vivo by inhibiting the interaction of b1 integrin with fibronectin. A mutatedGAS3,which is unable to bindb1 integrin,was also unable to inhibitfibronectin-mediated attachment and cell growth both in adherent and suspension cultures, suggesting that GAS3 exerts its effects through interaction with and regulation of b1 integrin. Thus, mda-7/IL-24 inhibits breast cancer growth, at least in part, through upregulation of GAS3 and disruption of b1 integrin function. Importantly, the expression of the mda-7/IL-24 receptor, IL-20R1, is highly correlated with GAS3 expression in human breast cancer (P1⁄4 1.02 10 ), and the incidence of metastases is significantly reduced in patients with HER2þ breast cancer expressing high-levels of IL20R1. Together, our results identify a novel MDA-7/IL-24-GAS3-b1integrin–fibronectin signaling pathway that suppresses breast cancer growth and can be targeted for therapy.Mol Cancer Res; 11(6); 593–603. 2013 AACR.