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The Effect of IKKbeta on Estrogen Receptor Positive Breast Cancer Phenotypes

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posted on 18.02.2018 by Lamiaa K. El-Shennawy
Estrogen receptor α (ER) is a good prognostic marker expressed in ~75% of breast tumors. Women with ER+ tumors will receive endocrine therapy, yet ~50% will experience relapse and late recurrence ~5-20 years after primary diagnosis. The recurrent tumors are often aggressive, resistant, and metastatic. A growing body of evidence suggests that an inflammatory microenvironment and the activation of the NF-ĸB pathway are highly associated with the progression of ER+ tumors to more aggressive stages. However, it is unknown whether NF-ĸB is a driver or a consequence of aggressive ER+ disease. In order to study this, we developed multiple ER+ breast cancer cell lines expressing a Doxycycline-inducible, constitutively active form of IĸB kinase β (CA-IKKβ), a key kinase in the canonical NF-ĸB pathway. This allowed us to specifically activate the canonical arm of the NF-ĸB pathway in a controlled fashion. Using these cells, we found that CA-IKKβ blocks E2-dependent cell proliferation in vitro and tumor growth in vivo. However, ER and CA-IKKβ work together to promote cell survival. These results, in conjunction with the finding that the anti-proliferative effects of CA-IKKβ are reversible, both in vitro and in vivo, suggest the possibility that CA-IKKβ induces dormant ER+ disease. Moreover, we found that the co-activation of ER and the canonical NF-ĸB pathway promote cell migration and invasion in vitro, through a mechanism involving expansion of a basal-like cell population, as well as both spontaneous and experimental metastasis in vivo. Together, these findings suggest that coactivation of ER and the canonical arm of the NF-ĸB pathway may promote a dormant, metastatic phenotype in ER+ breast cancer. These findings also implicate IKKβ as a driver of certain features of aggressive ER+ breast cancer and suggest IKKβ as both a potential biomarker and a novel therapeutic target in ER+ breast cancer.

History

Advisor

Frasor, Jonna

Department

Biopharmaceutical Sciences

Degree Grantor

University of Illinois at Chicago

Degree Level

Doctoral

Committee Member

Tonetti, Debra Hanakahi, Leslyn Prins, Gail Swanson, Steven

Submitted date

2015-12

Language

en

Issue date

17/02/2016

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