**4. Gene expression regulation at the level of mRNA stability**

It has been demonstrated that the stability of many messenger RNAs (mRNAs) encoding oncoproteins, chemokines, cytokines, and other inflammatory mediators is controlled by AU-rich elements (AREs), sequences located within the 3'-UTR of many transcripts [29, 30]. AREdirected control of mRNA decay is mediated, in part, through interactions with specific AREbinding proteins (AUBPs). One such protein is tristetraprolin (TTP), which accelerates the decay of targeted transcripts [31]. During inflammation, TTP plays a relevant role destabilizing different mRNAs, participating in glucocorticoid-mediated anti-inflammatory activity [32–34] and inhibiting NF-κB signaling [35]. The relevance of TTP as a negative regulator of these processes has been demonstrated by the severe chronic inflammation displayed by multiple tissues in TTP-KO mice, which was mostly due to the dramatic increase of TNF-α levels [32].

Several reports indicate that TTP participates in the inhibition of tumor progression. It has been shown that TTP mRNA levels are significantly decreased in many tumor types, including breast cancer [36]. We have also reported that TTP expression is lower in all breast cancer types compared with normal mammary tissue, and high levels of this protein negatively correlate with cancer cell aggressiveness. Interestingly, we have also determined that in the mouse mammary gland, expression of this protein reaches the highest level during lactation, and can be induced in culture by treatment with lactogenic hormones [37].

These studies reveal a new potential biological role for this tumor suppressor protein in mammary epithelium, since TTP might protect the tissue from inflammatory and/or remodeling activities that would trigger involution of the gland. Interestingly, our unpublished results show that by reducing TTP expression in the differentiated mammary epithelium, cell death is induced in the midst of lactation without requirement of additional stimuli. Then, TTP is not (or at least not only) a mechanism of surveillance, which prevents an eventual increase of inflammatory factors that might lead lactation to a halt, but it actually functions as a survival factor in the mammary epithelium, since reducing its levels is enough to induce cell death and involution of this tissue.
