IRF6, a member of Interferon Regulatory Factors (IRF) family, is involved in orofacial and epidermal development. In breast cancer cell lines ectopic expression of IRF6 reduces cell numbers suggesting a role as negative regulator of cell cycle. IRF6 is a direct target of canonical Notch signaling in keratinocyte differentiation. Notch is involved in luminal cell fate determination and stem cell regulation in the normal breast and is implicated as an oncogene in breast cancer. Notch activation is sufficient to induce proliferation and transformation in non-tumorigenic breast epithelial cell line, MCF10A. ΔNp63, which is downregulated by Notch activation in the breast, regulates IRF6 expression in keratinocytes. In this report, we investigate Notch-IRF6 and ΔNp63-IRF6 interactions in MCF10A and MDA MB 231 cells. We observed that in these cells, IRF6 expression is partially regulated by canonical Notch signaling and ΔNp63 downregulation. Furthermore, we demonstrate that IRF6 abrogation impairs Notch-induced proliferation and transformation in MCF10A cells. Thus, we confirm the previous findings by showing a tissue independent regulation of IRF6 by Notch signaling, and extend them by proposing a context dependent role for IRF6, which acts as a positive regulator of proliferation and transformation in MCF10A cells downstream of Notch signaling.