Tristetraprolin (TTP) Expression is Required for Mammary Progenitor Cell Survival

STEDILE MICAELA; BECKERMAN INÉS; GARCIA SOLA MARTIN; GODDIO MV; PEREZ CUERVO L; ANA RAIMONDI; KORDON EDITH

CABA

Simposio; BA-BCS 2021; 2021

Messenger RNA (mRNA) stability is regulated by proteinsthat bind to their 3´untranslated regions. One of them,Tristetraprolin (TTP), coded by Zfp36 gene, producesmRNA degradation of proteins involved in inflammation andtumorigenesis. We have previously proved that Wap-Crex TTPfl/fl mice display apoptosis of mammary epithelialcells in which Zfp36 had been deleted during lactation.Here, we show that parity-induced mammary epithelial progenitorcells are particularly affected in those bi-transgenicfemales, since they display underdeveloped alveoli in theirsecond lactation. Besides, multiparous females WAP-Cre xTTPfl/fl crossbred with RasG12D+/- mice presented fewerpre-neoplastic lesions than RasG12D+/- controls. Supportingthe relevance of TTP expression in undifferentiatedmammary cells, mRNA-seq data assessment indicates thatprogenitor populations display higher levels of Zfp36 thandifferentiated cells. Moreover, stem-like HC11 mammarycell line stably transfected with TTP-shRNA, exhibiteddecreased capacity to form mammospheres (MS) and torepopulate cleared fat pads. This phenotype was associatedwith high expression of pro-inflammatory cytokinesas well as p38, NFkB, STAT3 and Caspase 3 activation.We also found that MS formation capacity was increasedblocking TNFα or inhibiting p38 phosphorylation. In summary,our results indicate that TTP plays a relevant rolein mammary progenitor cell survival, by keeping in linestress-associated pathways.