Crosstalk of TTC5 cofactor and the estrogen receptor in breast cancer

The estrogen receptor (ER) is a transcription factor that regulates a wide array of genes and whose activity is a determinant for the prognosis of diseases such as breast cancer. ER, through L-X-X-L-L (L=leucine, X=any amino acid) motifs, interacts with cofactors such as TTC5 (tetratricopeptide repeat domain 5) which is a 440 amino acid protein, predicted to have 6 TPR (tetratricopeptide repeat) motifs and 4 LXXLL motifs, which are known to mediate protein-protein interactions. TTC5 has been shown previously to interact with and regulate the glucocorticoid receptor, which belongs to the same family of nuclear hormone receptors as ER. Thus, this provided the basis for the investigation of the role of TTC5 in ER signalling. This investigation revealed that TTC5 interacts with estrogen receptor alpha (ERa) in MCF-7 and T47D breast cancer cells, and that ER transcriptional activity on an estrogen response element was regulated by different TPR and LXXLL motifs of TTC5 in a cellspecific manner. Partial knockdown of TTC5 via siRNA led to a decrease of proliferation in cells treated with 17b-estradiol (E2), raloxifene and tamoxifen, indicating a potential role for TTC5 in breast cancer progression and survival. Effects of TTC5 silencing on cyclin D1 makes this molecule a candidate for inhibiting cyclin D1 gene expression. In summary, this thesis uncovers TTC5 as a novel regulatory factor of ER function, and identifies effects of TTC5 on cell proliferation. These key findings enhance our understanding of ER signalling which, given its importance for diseases such as breast cancer, may have important clinical implications for instance through targeting of TTC5.