TRISTETRAPROLIN (TTP) EXPRESSION IS REQUIRED FOR MAINTENANCE OF THE MAMMARY PROGENITOR CELL POPULATION

STEDILE MICAELA; BECKERMAN, INES; GODDIO V.; PEREZ CUERVO, LOURDES; MARTIN GARCIA SOLÁ; MEDINA VICTORIA; RAIMONDI ANA; OMAR COSO; EDITH KORDON

LXII Reunión Annual de la Sociedad Argentina de Investigación Clínica (SAIC Mar del Plata,

Congreso; LXII Reunión Annual de la Sociedad Argentina de Investigación Clínica (SAIC Mar del Plata,; 2019

SAIC

TRISTETRAPROLIN (TTP) PROMOTES SURVIVAL OF PROGENITOR MAMMARY EPITHELIAL CELLSStedile, Micaelaa; Goddio, María Victoriaab; Pérez Cuervo, Lourdesab; Beckerman, Inésa; García Solá, Martína; Kordon, Edithab.a Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE).bDepartamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, UBA.e-mail: micaela.stedile@gmail.com Stability of many mRNAs coding for proteins involved in inflammation, cell proliferation and invasiveness is regulated, among other factors, by proteins that bind their 3´untranslated regions (3´UTR). One of these proteins is Tristetraprolin (TTP) that promotes degradation of those mRNAs. 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, which involves TNF alpha, IL-6 and LIF increase, 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 was also underscored by its expression profile in the non-lactating mouse mammary gland. In silico analysis showed that 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 progenitor cell death driven by TTP loss. Preliminary results suggest the involvement of beta-catenin and the NF kappa B pathway. Taking together, these results indicate that TTP expression is required for survival of both mammary functional fully differentiated as well as progenitor cells.Key words: tristetraprolin, cell survival, apoptosis, mammary gland.