Nuclear tristetraprolin acts as a corepressor of multiple steroid nuclear receptors in breast cancer cells

Mol Genet Metab Rep. 2016 Mar 22;7:20-6. doi: 10.1016/j.ymgmr.2016.02.004. eCollection 2016 Jun.

Abstract

Tristetraprolin (TTP) is a 34-kDa, zinc finger-containing factor that in mammalian cells acts as a tumor suppressor protein through two different mechanisms. In the cytoplasm TTP promotes the decay of hundreds of mRNAs encoding cell factors involved in inflammation, tissue invasion, and metastasis. In the cell nucleus TTP has been identified as a transcriptional corepressor of the estrogen receptor alpha (ERα), which has been associated to the development and progression of the majority of breast cancer tumors. In this work we report that nuclear TTP modulates the transactivation activity of progesterone receptor (PR), glucocorticoid receptor (GR) and androgen receptor (AR). In recent years these steroid nuclear receptors have been shown to be of clinical and therapeutical relevance in breast cancer. The functional association between TTP and steroid nuclear receptors is supported by the finding that TTP physically interacts with ERα, PR, GR and AR in vivo. We also show that TTP overexpression attenuates the transactivation of all the steroid nuclear receptors tested. In contrast, siRNA-mediated reduction of endogenous TTP expression in MCF-7 cells produced an increase in the transcriptional activities of ERα, PR, GR and AR. Taken together, these results suggest that the function of nuclear TTP in breast cancer cells is to act as a corepressor of ERα, PR, GR and AR. We propose that the reduction of TTP expression observed in different types of breast cancer tumors may contribute to the development of this disease by producing a dysregulation of the transactivation activity of multiple steroid nuclear receptors.

Keywords: AR, androgen receptor; Androgen; Breast cancer; Corepressor; ERα, estrogen receptor; Estrogen; GR, glucocorticoid receptor; Glucocorticoid; Nuclear receptor; PR, progesterone receptor; Progesterone; TTP, tristetraprolin; Transactivation activity; Tristetraprolin.