Role of Irf6 as a Mediator of Notch Signaling in Breast Cancer Cell Lines

Abstract

Notch signaling is an evolutionary conserved pathway involved in development and differentiation. Disregulated Notch signaling is involved in cancer by showing tumor supressor or oncogenic properties. Notch signaling has firstly been described in breast cancer by the activation of Notch4 locus. Expression of a constitutively active form of Notch1 induces neoplasms and high level expression of Notch1 is observed in human breast cancer which indicate that Notch is an oncogene in breast tissue. However, recently it has been shown that Notch activation can decrease cell proliferation in human breast epithelial cells. The downstream mechanisms of Notch signaling that elicit oncogenic or tumor suppressor roles remain elusive. IRF6, a member of interferon regulatory factors, has been characterised as a novel Notch target gene involved in keratinocyte differentiation. IRF6 has been stated as a potential tumor suppressor in collaboration with Maspin in mammary epithelial cells. In this project, it was investigated whether IRF6 expression is regulated by Notch signaling in breast epithelial cells and whether it is a mediator of Notch in cell proliferation and transformation. It was shown that activation of Notch signaling in normal breast epithelial cell line MCF10A, increased expression of IRF6, while inhibition of Notch signaling in breast cancer cell line MDA-MB-231 reduced IRF6 levels. IRF6 silencing reduced Notch induced cell transformation in MCF10A cells but did not result in significant change in proliferation. These results indicate that IRF6 is a downstream target of Notch and functions as a mediator for Notch signaling in breast epithelial cells.