Abstract B43: APOBEC3B upregulation by the PKC-NFκB pathway in breast cancer

Overexpression of the antiviral DNA cytosine deaminase APOBEC3B has been linked to somatic mutagenesis in breast and other cancer. Human papillomavirus (HPV) infection accounts for APOBEC3B upregulation in cervical and head/neck cancers. However, the responsible mechanisms are unclear for non-viral malignancies such as breast cancer. Here, we demonstrate APOBEC3B upregulation through the PKC-NFκB pathway. PKC activation by the diacylglycerol mimic PMA causes specific and dose-responsive increases in APOBEC3B mRNA, protein, and activity levels, which are strongly suppressed by PKC and NFκB inhibition. Induction correlates with RELB (but not RELA) recruitment to the endogenous APOBEC3B gene implicating non-canonical NFκB signaling. Relevance to tumors is supported by PKC inhibitor-mediated APOBEC3B downregulation in multiple breast cancer cell lines. These data establish the first mechanistic link between APOBEC3B and a common signal transduction pathway, suggesting that existing PKC-NFκB inhibitors could be repurposed to suppress cancer mutagenesis, dampen tumor evolution, and decrease the probability of adverse outcomes such as drug resistance and metastases. Citation Format: Brandon Leonard, Jennifer McCann, Gabriel Starrett, Leah Kosyakovsky, Molan Amy, Michael Burns, Rebecca McDougle, Peter Parker, William Brown, Reuben Harris. APOBEC3B upregulation by the PKC-NFκB pathway in breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr B43.