Date of Award
PhD (Doctor of Philosophy)
Professor Leonie Young
Professor Arnold Hill
Breast Neoplasms, Genetics, Tamoxifen
Introduction: Biological targeted therapies have become a mainstay of breast cancer treatment for many patients. Tamoxifen is one of the most successful therapies to date due its anti-estrogenic effect in the breast. However, a significant number of patients, almost 40%, develop resistance to Tamoxifen therapy and are thus non responsive to its effects or in some cases, the tumour can actually progress on Tamoxifen. The steroid receptor coactivator 1 (SRC-1) has been associated with the development of Tamoxifen resistance in cellular models and in clinical patient populations. Furthermore, Tamoxifen treatment can upregulate SRC-1 activity in a resistant environment. SRC-1 has been shown to form a non steroidal transcriptional complex with the developmental protein, HOXC11; together they work to assist the deregulation of anti-tumourigenic signalling pathways within a tumour cell. SRC- 1/HOXC11 activity in endocrine resistance has been reported as a significant marker of poor prognosis in a clinical patient population. Currently, the secreted protein, S100P is the only identified target gene of SRC-1/HOXC11 activity in endocrine resistant breast cancer. Given the clinical relevance of this functional interaction, it is important to identify additional target genes in order to gain a greater insight into the effector pathways being regulated, as a tumour cell is driven from a responsive to a resistant state.
Hypothesis: SRC-1 has been upheld as a master regulator in cancer. It is well known for its ability to bind across unrelated families of transcription factors and coactivate the regulation of multiple genes in multiple complex physiological states. On the basis of SRC-1 ChlPsequencing (ChlPseq) and SRC-1 knockout DNA microarray data conducted in an endocrine resistant cellular model, this work hypothesises that SRC-1 can juxtapose its functionality between that of a coactivator and that of a corepressor depending on the transcriptional milieu. In this way, SRC-1 can have as significant an impact on tumour progression through the downregulation of "protective" genes as it could through the upregulation of its better characterised "progressive" genes. It is also hypothesised that HOXC11 is a common transcription factor of choice for SRC-1 in both transcriptional scenarios.
Results:Global analysis of SRC-1 in conjunction with a SRC-1 knockout DNA microarray identified 1,061 genes which were directly suppressed by SRC-1 activity in Tamoxifen driven endocrine resistant breast cancer. The luminal marker, CD24 was identified as a significant target gene of SRC-1 negative regulation. The developmental protein, HOXC11, is recruited with SRC-1 to negatively regulate CD24. Additional target genes of SRC-l/HOXCll activity were subsequently identified via inclusion of HOXC11 ChlPseq data. The tumour suppressor gene, PAWR, was also shown to be negatively regulated by SRC-l/HOXCll activity in the same resistant context as CD24. These molecular observations were confirmed in a clinical patient population where loss of CD24 and PAWR associated with poor disease free survival.
Conclusion: Both CD24 and PAWR expression associate with the well differentiated, tightly controlled processes of cell adhesion and apoptosis, respectively. Targeted downregulation of proteins such as these, deregulates a cell and makes it increasingly vulnerable to tumourigenic signalling mechanisms. Together, SRC-l/HOXCll decommission important antitumourigenic pathways to induce a deregulated cellular state which is ultimately more vulnerable to the intentional and targeted pressure of uncontrolled growth signalling pathways.
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Walsh CA. The steroid receptor coactivator, SRC-1, can function as a transcriptional corepressor to selectively suppress anti-tumourigenic target genes in Tamoxifen resistant breast cancer. [PhD Thesis]. Dublin: Royal College of Surgeons in Ireland; 2012.