Mammary differentiation induces expression of Tristetraprolin, a tumor suppressor AU-rich mRNA-binding protein

Abstract

Tristetraprolin (TTP) is a RNA-binding protein that inhibits the expression of pro-inflammatory cytokines and invasiveness-associated genes. TTP levels are decreased in many different cancer types and it has been proposed that this protein could be used as a prognostic factor in breast cancer. Here, using publicly available DNA microarray datasets, "serial analysis of gene expression" libraries and qRT-PCR analysis, we determined that TTP mRNA is present in normal breast cells and its levels are significantly decreased in all breast cancer subtypes. In addition, by immunostaining, we found that TTP expression is higher in normal breast tissue and benign lesions than in infiltrating carcinomas. Among these, lower grade tumors showed increased TTP expression compared to higher grade cancers. Therefore, these data indicate that TTP protein levels would provide a better negative correlation with breast cancer invasiveness than TTP transcript levels. In mice, we found that TTP mRNA and protein expression is also diminished in mammary tumors. Interestingly, a strong positive association of TTP expression and mammary differentiation was identified in normal and tumor cells. In fact, TTP expression is highly increased during lactation, showing good correlation with various mammary differentiation factors. TTP expression was also induced in mammary HC11 cells treated with lactogenic hormones, mainly by prolactin, through Stat5A activation. The effect of this hormone was highly dependent on mammary differentiation status, as prolactin was unable to elicit a similar response in proliferating or neoplastic mammary cells. In summary, these studies show that TTP expression is strongly linked to the mammary differentiation program in human and mice, suggesting that this protein might play specific and relevant roles in the normal physiology of the gland.

Remodeling of Zn2+ homeostasis upon differentiation of mammary epithelial cells

“…1 Therefore, it is reasonable that cytosolic labile Zn 2+ would increase to meet the structural or functional needs of the upregulated cytosol-localized zincdependent proteins during mammary cell differentiation. Among the list of upregulated zinc-dependent genes at D day 6, we found genes which reportedly encode cytosolic proteins that play important or essential roles in cell differentiation or lactation, including the vitamin D receptor (VDR), 60 Peptidylglycine alphaamidating monooxygenase (PAM) 61 and tristetraprolin (TTP), [62][63][64] a zinc-finger mRNA-binding protein encoded by ZIP36. TTP is highly expressed in differentiated mammary cells and the lactating mammary gland.…”

Estrogenic activity of isoflavonoids from the stem bark of the tropical tree Amphimas pterocarpoides , a source of traditional medicines

“…It is possible that a deguelin-like downregulation of STAT3 phosphorylation, c-Myc or Survivin expression through inhibition of EGFR, c-Met or NF-kB signaling [50], regulation of xanthine oxidoreductase expression by protein tyrosine kinase and MAP kinase cascades [51] as well as the antioxidant function of isoflavones [52] could affect the differentiation process. Compounds that facilitate the switch of HC11 cells from proliferative to lactating stage are thought to negatively impact the modulation of oncogenic signaling in breast cancer, as exemplified for instance by the inverse association of HC11 cell differentiation markers Tristetraprolin and Xanthine oxidoreductase with tumor grade [53,54]. In addition, it has been reported that treatment of HC11 cells with lactogenic hormones and of human breast cancer cells with certain chemical agents induce similar morphological and molecular traits that are characteristic of differentiated ductal epithelial cells [55].…”

PIM2 interacts with tristetraprolin and promotes breast cancer tumorigenesis

“…PIM2 is a typical oncogene in many cancers, but TTP is reported as a tumor suppressor (Goddio et al, 2012;Swords et al, 2011). We therefore hypothesized that PIM2 might regulate TTP protein levels.…”