GLUCOCORTICOID RECEPTOR FUNCTION AND ITS ROLE IN TAMOXIFEN RESISTANCE
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The function of the glucocorticoid receptor (GR) is crucial for the development and proliferation of normal human breast cells. The primary activity of GR is in its binding to glucocorticoids and the subsequent activation of its transcriptional target genes. However, GR is also able to transcriptionally regulate target genes in the absence of ligand in EPH4 mouse mammary cells, which is termed the unliganded activity of GR. Unliganded GR stimulates the activity of the BRCA1 and CH25H promoters and is important in modulating apoptosis and cell growth. The activity of unliganded GR in normal human breast cell lines was investigated in this study in order to validate its regulatory role. Unliganded GR did not upregulate BRCA1 or CH25H expression in the human breast cell lines MCF-10A and 184-hTERT. As well, no novel target genes of unliganded GR were identified in normal human breast cells, however both PRLR and CDKN1A were found to be negatively regulated by liganded and possibly unliganded GR respectively. The second portion of this study focused on the exploration of the role of GR in modulating tamoxifen response in ER+ breast cancer. GR was overexpressed in response to tamoxifen in ER+ breast cancer cells in the ER+ cell lines MCF-7 and T47D. As well, GSTM1 expression was increased by tamoxifen in a GR-dependent manner which suggests that downstream GR signaling is also increased in response to tamoxifen. This is crucial as it suggests that the increase in GR leads to increased GR activity and signaling. The ERα pioneer factor, FOXA1 was overexpressed by tamoxifen as well and may be responsible for activating GR overexpression. Finally, loss of GR may initiate a survival signal in ER+ cells as tamoxifen also increased the expression of cancer stem-like marker genes, EpCAM and ALDH1A3. EpCAM expression was found to be upregulated by tamoxifen and loss of GR expression and ALDH1A3 expression was increased 5-fold by tamoxifen alone. This upregulation of cancer stem-like markers suggests that tamoxifen resistance could occur through the formation of a stem-like chemotherapeutic resistant cell population.