LIVER X RECEPTOR (LXR) activation may affect breast cancer risk through induction of tristetraprolin (TTP) in mamary epithelial cells

Emilia Bogni¹, Diego Grinman², Sabrina Vallone¹, Albana Gatelli¹, Adali Pecci¹, Roberto Meiss³, Edith Kordon¹


Tristetraprolin (TTP), a protein coded by the Zfp36 gene, induces mRNA degradation of proteins involved in inflammation and tumorigenesis, while LXRa is a transcription factor that plays relevant roles in cholesterol and inflammation control. Our previous data show that both proteins are highly expressed and active in the mouse mammary epithelium during lactation. Besides, it has been proposed that a single nucleotide polymorphism, which may alter an LXR binding site in the human Zfp36 promoter region, is associated with lower TTP expression and worse prognosis in breast cancer patients. In order to analyze LXR role on TTP expression regulation in mammary cells, female mice were treated with the LXR agonist GW3965 (GW) or DMSO (control) by IP injection during 96h after weaning. Our results show that GW induced TTP, while inhibited IL-6, TNFa, LIF and S100A9 expression in the involuting glands. On the other hand, we analyzed the effects of GW as well as lactogenic hormones: glucocorticoids (Dex) and prolactin (Prl) on HC11 mouse mammary cells in culture. We found that both GW and Dex+Prl induced TTP and B-Casein mRNA expression. However, differently from the lactogenic hormones, GW did not trigger STAT5 phosphorylation. These results suggest that LXR may be involved in TTP expression regulation in the mammary gland through a STA5-independent mechanism. New experiments are underway to verify the impact of the LXR-TTP pathway on breast cancer progression.