Description
- Abstract:
- The aim of this body of research is to gain a more complete understanding of how 17β-estradiol (E2) drives the proliferation of breast cancer. This work achieves that goal by examining the extent and significance of E2 mediated post-transcriptional gene regulation, and by investigating how E2 coordinates transcriptional and post-transcriptional regulation. We have investigated post-transcriptional regulation of E2 response in the breast cancer cell line MCF-7, by performing genome-wide microarray analysis comparing total mRNA levels with that of monosomal and polysomal mRNA levels after E2 treatment. We observed several significant, novel findings. We found that polysome analysis has higher sensitivity than total RNA analysis in detecting E2-regulated transcripts, and it allowed us to discover several transcripts and pathways regulated by E2 at the translation level. This increased experimental sensitivity is exemplified by observations of stronger E2-induced enrichment of E2 expression signatures in polysomes than in total RNA. We observed that the initial translation state is already high for E2 upregulated transcripts before E2 treatment and vice versa for E2 down-regulated transcripts. This suggests that the translation state anticipates potential E2-induced transcriptome levels. Our data have identified two transcription factors mediating E2 stimulation, SRY (sex determining region Y) box 2 (SOX2) is translationally repressed, while the expression of neuron-restrictive silencer factor (NRSF) target genes is repressed by E2. We have demonstrated that these two transcription factors mediate E2 stimulation of the cell cycle. Together, these data suggest that E2 stimulates breast cancer cells by regulating translation through multiple mechanisms. In sum, we show that polysome profiling of E2 regulation of breast cancer cells provides novel insights into hormone action, and can identify novel factors critical for breast cancer cell growth. To improve our understanding of the role of translation in endocrine therapy, we have also extended our analysis to explore tamoxifen (TAM) controlled translation regulation in order to identify directly regulated genes, and any potential sequences, involved in antiestrogen induced growth arrest.
- Notes:
- Thesis (Ph.D. -- Brown University (2011)
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Citation
Bronson, Michael W.,
"Estrogen Mediated Coordination of Post-Transcriptional Regulation"
(2011).
Molecular Biology, Cell Biology, and Biochemistry Theses and Dissertations.
Brown Digital Repository. Brown University Library.
https://doi.org/10.7301/Z0988589
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Molecular Biology, Cell Biology, and Biochemistry Theses and Dissertations
Theses and Dissertations for the Molecular Biology, Cell Biology, and Biochemistry department....