Coactivation of estrogen receptor and IKKb induces a dormant metastatic phenotype in ER-Positive breast cancer

Lamiaa El-Shennawy, Oleksii Dubrovskyi, Irida Kastrati, Jeanne M. Danes, Yiqun Zhang, Herbert E. Whiteley, Chad J. Creighton, Jonna Frasor

Research output: Contribution to journalArticlepeer-review

Abstract

A growing body of evidence suggests that the inflammatory NFkB pathway is associated with the progression of ERþ tumors to more aggressive stages. However, it is unknown whether NFkB is a driver or a consequence of aggressive ERþ disease. To investigate this question, we developed breast cancer cell lines expressing an inducible, constitutively active form of IkB kinase b (CA-IKKb), a key kinase in the canonical NFkB pathway. We found that CA-IKKb blocked E2-dependent cell proliferation in vitro and tumor growth in vivo in a reversible manner, suggesting that IKKb May contribute to tumor dormancy and recurrence of ERþ disease. Moreover, coactivation of ER and IKKb promoted cell migration and invasion in vitro and drove experimental metastasis in vivo. Gene expression profiling revealed a strong association between ER and CA-IKKb–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 NFkB pathway promotes a dormant, metastatic phenotype in ERþ breast cancer and implicates IKKb as a driver of certain features of aggressive ERþ breast cancer. Significance: The canonical NFkB pathway promotes expansion of stem/basal-like cells and a dormant, metastatic phenotype in ERþ breast cancer cells.

Original languageEnglish (US)
Pages (from-to)974-984
Number of pages11
JournalCancer Research
Volume78
Issue number4
DOIs
StatePublished - Feb 15 2018

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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