Role of Bcl3 in the normal and neoplastic mammary gland

• Main Author: Wakefield, Alison
• Published: Cardiff University 2011
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.585251

The NF-kB family of transcription factors have previously been shown to be elevated in many malignant diseases including breast cancer. NF-kB activation is strongly associated with signalling downstream of the epidermal growth factor (EGF) family of receptors in both aggressive EGFR-positive and ERBB2-positive breast cancer subtypes. These observations have led to much interest in the use of NF-kB inhibitors to suppress tumour progression in breast cancer patients. However, as NF-kB controls numerous functions in homeostasis there are significant risks associated with sustained global inhibition of NF-kB signalling. This investigation therefore aimed to determine whether inhibition of the NF-kB co-factor, B-Cell Lymphoma 3 (BCL3), would block the pro-tumourigenic function of NF-kB, while allowing it to retain its physiological functions in normal tissues. Deletion of BCL3 had no effect on the gross morphology or function of the mammary gland during the pregnancy cycle, although a subtle BCL3 dose-dependent effect was observed during involution whereby 8c/3+/" mice had increased apoptotic bodies in comparison with both 6c/3+/+ and Bcl3'h mice. Loss of BCL3 in the context of ERBB2-driven murine mammary carcinogenesis resulted in a significant delay in both the initiation and metastatic progression of mammary adenocarcinomas. Further in vitro investigation revealed that Bcl3 suppression by SiRNA in a murine mammary ERBB2- positive cell line reduced both the migratory and invasive capacity of cells, indicating that BCL3 was able, at least in part, to exert a pro-metastatic effect in a cell autonomous manner. In addition, SiRNA suppression of BCL3 reduced both the proliferative and migratory capacity of both ERBB2-positive and EGFR-positive human breast cancer cell lines. Collectively, these results suggest that targeting BCL3 may be an effective therapeutic strategy in the treatment of both ERBB2- and EGFR-positive breast cancers.