Coactivation of Estrogen Receptor and IKKβ Induces a Dormant Metastatic Phenotype in ER-Positive Breast Cancer

Abstract

A growing body of evidence suggests that the inflammatory NFκB pathway is associated with the progression of ER⁺ tumors to more aggressive stages. However, it is unknown whether NFκB is a driver or a consequence of aggressive ER⁺ disease. To investigate this question, we developed breast cancer cell lines expressing an inducible, constitutively active form of IκB kinase β (CA-IKKβ), a key kinase in the canonical NFκB pathway. We found that CA-IKKβ blocked E2-dependent cell proliferation <i>in vitro</i> and tumor growth <i>in vivo</i> in a reversible manner, suggesting that IKKβ may contribute to tumor dormancy and recurrence of ER⁺ disease. Moreover, coactivation of ER and IKKβ promoted cell migration and invasion <i>in vitro</i> and drove experimental metastasis <i>in vivo</i> Gene expression profiling revealed a strong association between ER and CA-IKKβ-driven gene expression and clinically relevant invasion and metastasis gene signatures. Mechanistically, the invasive phenotype appeared to be driven by an expansion of a basal/stem-like cell population rather than EMT. Taken together, our findings suggest that coactivation of ER and the canonical NFκB pathway promotes a dormant, metastatic phenotype in ER⁺ breast cancer and implicates IKKβ as a driver of certain features of aggressive ER⁺ breast cancer.<b>Significance:</b> The canonical NFκB pathway promotes expansion of stem/basal-like cells and a dormant, metastatic phenotype in ER⁺ breast cancer cells. <i>Cancer Res; 78(4); 974-84. ©2017 AACR</i>.