TRISTETRAPROLIN (TTP) PROMOTES SURVIVAL OF PROGENITOR MAMMARY EPITHELIAL CELLS

MICAELA STEDILE; MARÍA VICTORIA GODDIO; LOURDES PEREZ CUERVO; INES BECKERMAN; MARTIN GARCIA SOLÁ; EDITH C KORDON

Simposio; SISTAM 2018; 2018

Messenger RNA (mRNA) stability is regulated, among other factors, by proteins that bind sequences enriched in adenine and uracil (AREs) in their 3 ́untranslated regions (3 ́UTR). One of these proteins is Tristetraprolin (TTP), which promotes degradation of mRNAs that code for proteins involved in inflammation, proliferation and invasiveness. We have previously reported that TTP expression is down-regulated in breast cancer compared to normal gland, where TTP reaches its highest levels during lactation. Interestingly, knocking-down TTP expression during that period resulted in cell death and early initiation of post-lactational involution, associated with TNF alpha, IL-6 and LIF induction as well as STAT3 phosphorylation. Our more recent results indicate that TTP is also necessary for survival of mammary progenitor cells. First, we found that mammary transplants from TTP-KO mice into wild-type females showed under-developed branching morphogenesis. Then, we determined that TTP deletion in pregnancy-induced mammary progenitor cells (PI-MECs) caused dramatic inhibition of alveolar development in the following lactation. The relevance of TTP in the progenitor population is also underscored by its expression profile in the non- lactating mouse mammary gland. In silico analysis shows TTP expression is higher in both ductal and alveolar luminal progenitors than in their mature counterparts. In addition, TTP down-regulation in HC11 mammary cells, a line that exhibits stem-cell features, resulted in diminished viability and apoptosis induction, associated with Bax protein expression. We are presently analyzing the mechanisms underlying cell death driven by TTP loss. Our preliminary results show an increase of phosphorylated p65 (P-RelA) as well as beta-catenin levels. Taking together, these results indicate that TTP expression is relevant for both mammary fully differentiated and progenitor cell survival.