TY - JOUR
T1 - Coactivation of estrogen receptor and IKKb induces a dormant metastatic phenotype in ER-Positive breast cancer
AU - El-Shennawy, Lamiaa
AU - Dubrovskyi, Oleksii
AU - Kastrati, Irida
AU - Danes, Jeanne M.
AU - Zhang, Yiqun
AU - Whiteley, Herbert E.
AU - Creighton, Chad J.
AU - Frasor, Jonna
N1 - Publisher Copyright:
© 2017 American Association for Cancer Research.
PY - 2018/2/15
Y1 - 2018/2/15
N2 - 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.
AB - 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.
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U2 - 10.1158/0008-5472.CAN-17-1686
DO - 10.1158/0008-5472.CAN-17-1686
M3 - Article
C2 - 29229606
AN - SCOPUS:85042183072
SN - 0008-5472
VL - 78
SP - 974
EP - 984
JO - Cancer Research
JF - Cancer Research
IS - 4
ER -