Update on the Role of NFκB in Promoting Aggressive Phenotypes of Estrogen Receptor-Positive Breast Cancer

Abstract

The majority of breast cancers are diagnosed as estrogen receptor-positive (ER+) and respond well to ER-targeted endocrine therapy. Despite the initial treatability of ER+ breast cancer, this subtype still accounts for the majority of deaths. This is partly due to the changing molecular characteristics of tumors as they progress to aggressive, metastatic, and frequently therapy resistant disease. In these advanced tumors, targeting ER alone is often less effective, as other signaling pathways become active, and ER takes on a redundant or divergent role. One signaling pathway whose crosstalk with ER has been widely studied is the nuclear factor kappa B (NFκB) signaling pathway. NFκB is frequently implicated in ER+ tumor progression to an aggressive disease state. Although ER and NFκB frequently co-repress each other, it has emerged that the 2 pathways can positively converge to play a role in promoting endocrine resistance, metastasis, and disease relapse. This will be reviewed here, paying particular attention to new developments in the field. Ultimately, finding targeted therapies that remain effective as tumors progress remains one of the biggest challenges for the successful treatment of ER+ breast cancer. Although early attempts to therapeutically block NFκB activity frequently resulted in systemic toxicity, there are some effective options. The drugs parthenolide and dimethyl fumarate have both been shown to effectively inhibit NFκB, reducing tumor aggressiveness and reversing endocrine therapy resistance. This highlights the need to revisit targeting NFκB in the clinic to potentially improve outcome for patients with ER+ breast cancer.

Keywords: ER+ breast cancer; NFκB pathway; endocrine resistance; tumor recurrence.

Figure 1.

Schematic demonstrating phenotypic and clinical implications of ER-NFκB crosstalk in ER+ breast cancer. Activation of NFκB in ER+ tumors has been implicated in stem, EMT/invasive, and drug tolerant and resistant phenotypes and associated with reduced overall survival, disease relapse, and metastasis. The drugs DMF, ACT001, and didox have been shown to block NFκB signaling in preclinical models of ER+ breast cancer.