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

ABSTRACT: A growing body of evidence suggests that the inflammatory NF?B pathway is associated with the progression of ER+ tumors to more aggressive stages. However, it is unknown whether NF?B 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 I?B kinase ? (CA-IKK?), a key kinase in the canonical NF?B pathway. We found that CA-IKK? blocked E2-dependent cell proliferation in vitro and tumor growth in vivo in a reversible manner, suggesting that IKK? may contribute to tumor dormancy and recurrence of ER+ disease. Moreover, coactivation of ER and IKK? promoted cell migration and invasion in vitro and drove experimental metastasis in vivo Gene expression profiling revealed a strong association between ER and CA-IKK?-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 NF?B pathway promotes a dormant, metastatic phenotype in ER+ breast cancer and implicates IKK? as a driver of certain features of aggressive ER+ breast cancer.Significance: The canonical NF?B pathway promotes expansion of stem/basal-like cells and a dormant, metastatic phenotype in ER+ breast cancer cells. Cancer Res; 78(4); 974-84. ©2017 AACR.

SUBMITTER: El-Shennawy L 

PROVIDER: S-EPMC5815896 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature