Tristetraprolin promotes mammary progenitor cell survival by inhibiting the TNFα-p38 signaling pathway

MICAELA STEDILE; LARA, ANGELA; GARCÍA SOLÁ MARTÍN; BECKERMAN INÉS; BOGNI EMILIA; MARINA AYRE; COSO OMAR; EDITH C KORDON

Rodas

Congreso; 8 th International Conference on Tumor Microenvironment and Cellular Stress; 2022

Aegean Conferences

Tristetraprolin (TTP) is a protein that binds specifically to mRNAs of proteins involved in inflammation (as TNF or IL-6), proliferation and tumor invasiveness, promoting their degradation. We have previously reported that TTP expression is lower in invasive breast cancer compared to normal mammary gland and, in mice this protein reaches its highest level during lactation. In addition, we found that WAP-Cre x TTP fl/flfemale mice (MG TTP-KO), showed early initiation of post-lactational involution. On the other hand, public data analysis indicate that Claudin-low mammary tumors do not show TTP down regulation, and in Triple Negative Breast Cancer (TNBC) patients, TTP high expression is associated with lower survival rate. In mice, single cell RNAseq data analysis shows that mammary progenitor cell populations display relatively higher TTP levels. We have determined that, upon successive pregnancies, mammary glands of MG TTP-KO mice exhibits underdeveloped alveoli, which suggests impairment of the pregnancy-induced mammary progenitor cell population. Moreover, TTP partial silencing in the stem-like HC11 mammary cell line (TTP-KD) induced apoptosis, reduced mammosphere formation, and a significant impairment of in vivo cleared fat-pad repopulation as well as increased Il-6 and TnfαmRNA, phospho-p65 RelA, phospho-STAT3 and phospho-p38 MAPK. Importantly,these features were also observed in mammary tissue of MG TTP-KO mice. Finally, in TTP-KD cells, secreted TNF blockade as well as p38 MAPK inhibition restored TTP activity and mammosphere formation in culture. Taking together, these results indicate that TTP prevents apoptosis induction by stress associated signaling in the mammary progenitor compartment and that activity might explain the worse prognosis observed in TNBC patients that display high levels of this protein. In addition, our data demonstrate the relevance of mRNA stability regulation in modulating the impact of stress on stem cell survival.