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 genesand 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 cofactorssuch 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 areknown to mediate protein-protein interactions. TTC5 has been shown previously tointeract with and regulate the glucocorticoid receptor, which belongs to the same familyof nuclear hormone receptors as ER. Thus, this provided the basis for the investigation ofthe role of TTC5 in ER signalling. This investigation revealed that TTC5 interacts with estrogen receptor alpha (ERa) inMCF-7 and T47D breast cancer cells, and that ER transcriptional activity on an estrogenresponse element was regulated by different TPR and LXXLL motifs of TTC5 in a cellspecificmanner. Partial knockdown of TTC5 via siRNA led to a decrease of proliferationin cells treated with 17b-estradiol (E2), raloxifene and tamoxifen, indicating a potentialrole for TTC5 in breast cancer progression and survival. Effects of TTC5 silencing oncyclin 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, andidentifies effects of TTC5 on cell proliferation. These key findings enhance ourunderstanding of ER signalling which, given its importance for diseases such as breastcancer, may have important clinical implications for instance through targeting of TTC5.
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