TY  - GEN
UR  - https://archiv.ub.uni-heidelberg.de/volltextserver/7453/
KW  - gene regulation 
KW  -  estrogen receptor alpha
TI  - Regulation of estrogen responsive genes by human Estrogen Receptor alpha
Y1  - 2007///
ID  - heidok7453
A1  - Bretschneider, Nancy
AV  - public
N2  - In women, breast cancer is the most common cancer and accounts for most cancer deaths. The molecular mechanisms underlying this pathology are diverse and contribute to the complexity of the disease. Early diagnosis and detailed molecular characterization of tumours significantly increase the prognosis for the patients. A limited number of breast cancer markers are already used for diagnosis, characterization, and determination of the most promising therapy of breast cancer tumours. Although new therapeutic approaches such as herceptin antibodies are now available on the market, new markers that are specific for a subset of breast cancer patients are urgently needed. A major criterion in breast cancer diagnosis is the presence of the estrogen receptor alpha (ER?) which is associated with better prognosis and often sensitivity to anti-estrogen therapy. ER? is a ligand-inducible transcription factor that modulates expression of estrogen responsive target genes involved in both, physiological and pathological conditions such as breast cancer. Despite the complexity of the regulatory mechanisms, a variety of mechanisms resulting in transcriptional activation of target genes have been characterised. Although about 50 % of estrogen-responsive genes are repressed in response to estrogen treatment, the mechanisms underlying this regulation are just beginning to be discovered. This thesis aimed to study expression and regulation of the breast cancer and salivary gland expression gene (BASE). The evaluation of this gene was interesting for two reasons: firstly, its expression is strongly repressed by estrogen suggesting involvement of ER?, and secondly, previous studies indicate that the expression of this putative secreted protein is restricted to breast cancer cells and salivary gland. Therefore, BASE has the potential to function as a new breast cancer marker. One major finding of this study is the strong separation of expression and regulation of BASE. Expression of the gene is depending on the transcription factor FoxA1, which binds in a regulatory region about 2 kb upstream of the transcription start site. Although essential for expression, FoxA1 has no function in BASE regulation. Furthermore, this study shows that the BASE gene is rapidly repressed after estrogen-treatment and that ER? is required for this regulation. ER? can bind the BASE promoter in the same regulatory region as FoxA1, however, direct binding seems not to be a critical prerequisite. Based on the data obtained in this study, two molecular models for the mechanism of repression are proposed. Furthermore, analysis of normal and primary breast tumour samples in collaboration with M. Kerins group in Galway confirmed BASE expression in about 50 % of the samples. Therefore, BASE remains an interesting candidate as breast cancer marker.  In a side project investigating the mechanism of estrogen mediated activation of target genes, the CTSD gene has been further characterized. Besides the well characterized proximal promoter, the functionality of two further ER? binding sites, located 9 kb and 33 kb upstream of the transcription start site, have been reported. This study confirmed binding of ER? and PolII to the 9 kb upstream enhancer and moreover, the ability of this site to convey estrogen-stimulation was confirmed. Whether the enhancer requires physical interaction with the proximal promoter to enable transcriptional activation remains to be further examined.
ER  -