Identification of an AP1-ZFP36 regulatory network associated with breast cancer prognosis

CANZONERI R; JULIAN NAIPAUER; RODRIGUEZ PEÑA A; LACUNZA EZEQUIEL; GANDINI ARIEL; CURINO A; FACCHINETTI M; OMAR A. COSO; EDITH C. KORDON; MARTIN ABBA

JOURNAL OF MAMMARY GLAND BIOLOGY AND NEOPLASIA

SPRINGER/PLENUM PUBLISHERS

Lugar: New York; Año: 2020

1083-3021

It has been established that ZFP36 (also known as Tristetraprolin or TTP) promotes30 mRNA degradation of proteins involved in inflammation, proliferation and tumor31 invasiveness. In mammary epithelial cells ZFP36 expression is induced by STAT532 activation during lactogenesis, while in breast cancer ZFP36 expression is associated33 with lower grade and better prognosis. Here, we show that the AP-1 transcription factor34 components, i.e. JUN, JUNB, FOS, FOSB, in addition to DUSP1, EGR1, NR4A1, IER235 and BTG2, behave as a conserved co-regulated group of genes whose expression is36 associated to ZFP36 in cancer cells. In fact, a significant down-modulation of this gene37 network is observed in breast, liver, lung, kidney, and thyroid carcinomas compared to38 their normal counterparts. In breast cancer, the normal-like and Luminal A, show the39 highest expression of the ZFP36 gene network among the other intrinsic subtypes and40 patients with low expression of these genes display poor prognosis. It is also proposed41 that AP-1 regulates ZFP36 expression through responsive elements detected in the42 promoter region of this gene. Culture assays show that AP-1 activity induces ZFP36expression in mammary cells in response to prolactin (PRL) treatment 43 thorough ERK1/244 activation. These results suggest that JUN, JUNB, FOS and FOSB are not only co45expressed, but would also play a relevant role in regulating ZFP36 expression in46 mammary epithelial cells.