CREB, cAMP responsive element binding protein is a positive regulatory protein transcriptional factor, for genes including aromatase, an enzyme that converts androgens to oestrogens, c-fos, tyrosine hydroxylase and neuropeptides like somatostatin and enkephalin. The expression of aromatase is highly aberrant in human breast cancer and has been implicated in the disease progression. Aromatase expression in breast cancer tissue is directed mainly by promoters 1.3 and II. CRE1 and CRE2 are essential for cAMP induced promoter II activity. CRE binding protein (CREB) bound to this element (CRE) and that this interaction was enhanced in the presence of cAMP. Despite the extensive work on aromatase, little information is available on the expression and role of CREB in human breast cancer. The aim of this study was to investigate the molecular impact of CREB family of proteins on the aggressive nature of breast cancer cells and to investigate the expression pattern in breast cancer tissues in relation to tumour histopathological grade, stage, nodal status and the clinical outcome of the patients. In this study we examined the expression of CREB1 and ATFs (Activating transcription factors) in breast cancer cell lines using RT-PCR, which allowed us to design the strategy of in vitro experiments. Ribozyme knockdown technology was used to target the expression of CREB1 in a breast cancer cell line MDA-MB-231. Knockdown of CREB1 using ribozyme transgenes resulted in decrease in in vitro cell growth and invasiveness in breast cancer cells. The results presented here demonstrate that the level of CREB-1 and ATFs in breast cancer patients was elevated. The study results presented here revealed a significant link between CREB and mortality, in that high levels are associated with shorter disease free survival and interestingly we found significantly low levels of ATFs in patients with poor prognosis, metastatic disease and nodal involvement. We conclude that the level of CREB-1 and ATFs are aberrantly expressed in human breast cancer which may be associated with disease progression in breast cancer patients and has significant bearing to the clinical outcome of the patients. Over-expression of aromatase in adipose tissue surrounding breast tumour could arise through increase in both CREB expression and CREB transcriptional activity. Inhibition of CREB activity could inhibit aromatase expression and hence decrease oestrogen production in breast tissue. An understanding of the molecular mechanisms of expression of CREB, together with aromatase between non-cancerous and cancerous breast tissue at both transcriptional and translational levels may help in the design of a therapy based on suppressing aromatase expression in breast cancer tissues.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:567388 |
| Date | January 2012 |
| Creators | Chhabra, Alok |
| Publisher | Cardiff University |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://orca.cf.ac.uk/38641/ |
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