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Cancer Res. 2018 Feb 15;78(4):974-984. doi: 10.1158/0008-5472.CAN-17-1686. Epub 2017 Dec 11.

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

Author information

1
Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, Illinois.
2
Department of Environmental Studies, Institute of Graduate Studies and Research, Alexandria University, Alexandria, Egypt.
3
Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas.
4
College of Veterinary Medicine, University of Illinois, Urbana, Illinois.
5
Department of Medicine, Baylor College of Medicine, Houston, Texas.
6
Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, Illinois. jfrasor@uic.edu.

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 in vitro and tumor growth in vivo 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 in vitro and drove experimental metastasis in vivo 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.Significance: The canonical NFκB 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.

PMID:
29229606
PMCID:
PMC5815896
DOI:
10.1158/0008-5472.CAN-17-1686
[Indexed for MEDLINE]
Free PMC Article

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