The RNA-destabilizing factor tristetraprolin (TTP) is induced by lactogenic hormones in the mammary epitheliu

M. VICTORIA GODDIO; ALBANA GATTELLI; VICTORIA SLOMIANSKY; JONATHAN LAMARRE; MARTIN ABBA ; EDITH C. KORDON

Il Ciocco, Barga

Congreso; Gordon Research Conference in Mammary Gland Biology; 2010

Gordon Research Conferences

    Adenylate uridylate-rich elements (ARE) are characteristic sequences in the 3’UTR of mRNAs that are recognized by ARE-binding proteins (AUBPs), which influence their stability. The best characterized AUBPs are: AUF1, HuR and TTP. Various genes, including several factors that regulate multiple physiological processes contain ARE sequences. Therefore, simultaneous alteration in mRNA transcription and stability of these factors can profoundly alter cell behavior in a very short time. Interestingly, we have observed differential AUBP expression during mammary gland development, indicating that these proteins may play significant and specific roles in this process. Particularly, TTP displayed the strongest level of induction during lactation. In addition, by immunohistochemistry (IHC) we found high TTP protein expression in the cytoplasm of luminal epithelium in lactating glands. We have also found that HC11 cell differentiation in culture elicited expression of both, endogenous TTP and a reporter luciferase gene placed under the control of a 600 bp mouse TTP promoter sequence.  The presence of prolactin was necessary to trigger lactogenic induction, since no effect was observed in cells treated only with dexamethasone. In agreement with these results, transfection with a Stat5a dominant negative mutant completely abolished TTP induction triggered by lactogenic hormones (dexamethasone, insulin and prolactin). To determine whether the observed association with mouse mammary gland differentiation showed any correlation with normal, hyperplastic and neoplastic human mammary glands, we analyzed a set of human breast tissue sections by IHC. We identified a statistical significant decrease in TTP protein expression from normal/hiperplastic human breast tissues to human invasive breast carcinomas Interestingly, we have also identified a significant association between high expression of TTP in normal-like breast carcinomas compared to the other breast cancer intrinsic subtypes. Therefore, we found that high levels of TTP correlated with mammary differentiation in mouse and humans. Since it has been already demonstrated that this AUBP is a potent negative regulator of inflammatory cytokines that play an important role during mammary gland involution, we propose that TTP expression would be relevant for maintaining the differentiated phenotype, preventing the early onset of mammary involution. In addition, our data suggest that loss of TTP expression would be associated to breast cancer progression.