Pax-5 Inhibits NF- κB Activity in Breast Cancer Cells Through IKKε and miRNA-155 Effectors

In this study, we set out to elucidate the regulatory network between differentialPax-5 expression and NF- κB activity which dictate breast cancer malignancy. Through next-generation sequencing (NGS) of breast cancer cells conditionally expressingPax-5, we profile significantly upregulated microRNAs; including microRNA-155, a known regulator of pathological processes and suppressor of malignant growth. Through the conditional expression of microRNA-155 in breast cancer models, we identify and validate IKK ε (IKBKE) as a downstream target and an essential effector ofPax-5-mediated suppression of NF- κB signaling. Using rescue experiments, we also confirm thatPax-5 modulates NF- κB activity via IKKε downregulation. Interestingly, we also show that microRNA-155, in turn, supressesPax-5 expression, indicative of an auto-regulatory feedback loop. Altogether, we demonstrate thatPax-5 inhibits NF- κB signalling through the regulation of microRNA-155 and its downstream target IKKε. The elucidation of this signaling network is relevant asPax-5 and NF- κB are potent transcriptional regulators of breast cancer aggressivity. In addition, IKKε is relevant oncogene aberrantly expressed in 30% of breast carcinomas. Further insight into the regulatory pathways of breast cancer progression will eventually identify strategic therapeutic and prognostic t argets to improve cancer patient outcome.
Source: Journal of Mammary Gland Biology and Neoplasia - Category: Cancer & Oncology Source Type: research