Identification of an AP1-ZFP36 Regulatory Network Associated with Breast Cancer Prognosis

Abstract

It has been established that ZFP36 (also known as Tristetraprolin or TTP) promotes mRNA degradation of proteins involved in inflammation, proliferation and tumor invasiveness. In mammary epithelial cells ZFP36 expression is induced by STAT5 activation during lactogenesis, while in breast cancer ZFP36 expression is associated with lower grade and better prognosis. Here, we show that the AP-1 transcription factor components, i.e. JUN, JUNB, FOS, FOSB, in addition to DUSP1, EGR1, NR4A1, IER2 and BTG2, behave as a conserved co-regulated group of genes whose expression is associated to ZFP36 in cancer cells. In fact, a significant down-modulation of this gene network is observed in breast, liver, lung, kidney, and thyroid carcinomas compared to their normal counterparts. In breast cancer, the normal-like and Luminal A, show the highest expression of the ZFP36 gene network among the other intrinsic subtypes and patients with low expression of these genes display poor prognosis. It is also proposed that AP-1 regulates ZFP36 expression through responsive elements detected in the promoter region of this gene. Culture assays show that AP-1 activity induces ZFP36 expression in mammary cells in response to prolactin (PRL) treatment thorough ERK1/2 activation. These results suggest that JUN, JUNB, FOS and FOSB are not only co-expressed, but would also play a relevant role in regulating ZFP36 expression in mammary epithelial cells.