The Effect of IKKbeta on Estrogen Receptor Positive Breast Cancer Phenotypes

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.