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

Abstract

Pax-5, an essential transcription factor in B cell development, is aberrantly expressed in various B cell cancer lesions and solid tumors such as breast carcinoma. We have recently shown that Pax-5 regulates NF-κB activity which lead to the modulation of breast cancer phenotypic features (EMT-MET). NF-κB is known as a central mediator in inflammation, stress response as well as being a gatekeeper of pro-tumorigenic activity. However, little is known as to how Pax-5 affects this modulation. We thus turned our attention to microRNAs as potential regulatory effectors. In this study, we set out to elucidate the regulatory network between differential Pax-5 expression and NF-κB activity which dictate breast cancer malignancy. Through next-generation sequencing (NGS) of breast cancer cells conditionally expressing Pax-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 IKKε (IKBKE) as a downstream target and an essential effector of Pax-5-mediated suppression of NF-κB signaling. Using rescue experiments, we also confirm that Pax-5 modulates NF-κB activity via IKKε downregulation. Interestingly, we also show that microRNA-155, in turn, supresses Pax-5 expression, indicative of an auto-regulatory feedback loop. Altogether, we demonstrate that Pax-5 inhibits NF-κB signalling through the regulation of microRNA-155 and its downstream target IKKε. The elucidation of this signaling network is relevant as Pax-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 targets to improve cancer patient outcome.

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Acknowledgements

We gladly acknowledge the support by grants from the New Brunswick (NB) Innovation Foundation; the Canadian Breast Cancer Foundation; the Beatrice Hunter Cancer Research Institute; the Canadian Breast Cancer Society/QEII Foundation; and, the NB Health Research Foundation. Salaries for JH and NL are supported by the Beatrice Hunter Cancer Research Institute with funds provided by the Terry Fox Strategic Health Research Training Program in Cancer Research at CIHR in partnership with the NB Health Research Foundation.

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Correspondence to Gilles A. Robichaud.

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Harquail, J., LeBlanc, N., Landry, C. et al. Pax-5 Inhibits NF-κB Activity in Breast Cancer Cells Through IKKε and miRNA-155 Effectors. J Mammary Gland Biol Neoplasia 23, 177–187 (2018). https://doi.org/10.1007/s10911-018-9404-4

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Keywords

  • Breast cancer
  • IKK
  • miRNA
  • Pax-5
  • NF-κB
  • Invasion
  • Migration
  • EMT/MET