CONICET | Buscador de Institutos y Recursos Humanos

Messenger RNA (mRNA) stability is regulated, among other factors, by proteins that bind sequences enriched in adenine and uracil in their 3´untranslated regions, called collectively AU-binding proteins (AUBPs). Tristetraprolin (TTP) is an AUBP, which promotes mRNA degradation of proteins involved in inflammation, proliferation and tumor invasiveness. We have previously reported that TTP expression is down-regulated in breast cancer compared to the normal mammary gland and, in mice, it reaches its highest levels during lactation. In addition, we found that bi-transgenic female mice (WAP-Cre x TTPfl/fl), named MG TTP-KO, showed early initiation of post-lactational involution. These mice displayed TNF alpha, IL-6 and LIF increased expression, STAT3 activation and cell death induction by day 15 of lactation. Recently, we have observed that upon successive pregnancies mammary glands of MG TTP-KO mice exhibited underdeveloped lactating glands, which suggested impairment of the pregnancy-induced mammary progenitor cell population. Besides, in glands of triple transgenic female mice, we determined that TTP deletion led to inhibition of Ras oncogenic effects. Moreover, the effects of TTP down-regulation were also demonstrated in the stem-like HC11 mammary cell line, in which partial silencing of that gene caused apoptosis in culture and a significant impairment of their ability for repopulating cleared fat-pads in vivo. Presently, we are analyzing signaling pathways induced by different TTP targets, which are overexpressed in the mammary cells of MG TTP-KO mice, as TNF alpha, which might lead to progenitor cell death. Taking together, these results indicate that TTP expression is required for the maintenance of the mammary progenitor cell population. Besides, we are showing, for the first time, that AUBPs and stability regulation of specific mRNAs play central roles in mammary progenitor cell survival and proliferation.