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dc.contributor.advisorRahimi, Naderen_US
dc.contributor.authorShafran, Jordan Sethen_US
dc.date.accessioned2020-06-02T15:21:27Z
dc.date.available2020-06-02T15:21:27Z
dc.date.issued2020
dc.identifier.urihttps://hdl.handle.net/2144/41118
dc.description.abstractThe inevitable progression of advanced prostate cancer to castration resistance, and ultimately to lethal metastatic disease, depends on primary or acquired resistance to conventional androgen-deprivation therapy (ADT) and accumulated resistance mechanisms to evade androgen receptor (AR) suppression. Whereas the canonical androgen/AR signaling axis maintains prostate cell growth, differentiation and survival, in prostate cancer cells, AR adaptations that arise in response to ADT are not singular, but diverse, and include gene amplification, mutation and even complete loss of receptor expression. Collectively, each of these AR adaptations contributes to a complex, heterogenous, ADT-resistant tumor that culminates in prostate tumor cells transitioning from epithelial to mesenchymal states (EMT) and the development of metastatic castration-resistant prostate cancer (mCRPC). Here, we examined prostate cancer cell lines that model common CRPC subtypes, each with different AR composition, and focused on novel regulators of tumor progression, the Bromodomain and ExtraTerminal (BET – BRD2, BRD3 and BRD4) family of proteins, to test the hypothesis that each BET family member regulates EMT and underlying characteristics such as cell motility and invasiveness. We systematically manipulated the BET proteins and found that BRD4 regulates cell migration and invasion across all models of CRPC, regardless of aggressiveness and AR status, whereas BRD2 and BRD3 only regulate cell migration and invasion in less aggressive models that retain AR expression or signaling. We determined that BRD4’s contribution to this process occurs through the transcriptional regulation of AHNAK, SNAI1 and SNAI2, which are EMT genes linked to promotion of metastasis in a diverse set of cancers. Furthermore, treatment of CRPC cell lines with low doses of MZ1, a small-molecule, BRD4-selective degrader, inhibits EMT and metastatic potential. Overall, these results reveal a novel, BRD4-regulated EMT gene signature that may be targetable to treat metastatic castration-resistant prostate cancer.en_US
dc.language.isoen_US
dc.subjectMolecular biologyen_US
dc.subjectAHNAKen_US
dc.subjectBET proteinsen_US
dc.subjectBRD4en_US
dc.subjectEpithelial to mesenchymal transition (EMT)en_US
dc.subjectProstate canceren_US
dc.subjectSnail and slugen_US
dc.titleThe role of BET proteins in castration-resistant prostate cancer disseminationen_US
dc.typeThesis/Dissertationen_US
dc.date.updated2020-06-01T22:04:18Z
etd.degree.nameDoctor of Philosophyen_US
etd.degree.leveldoctoralen_US
etd.degree.disciplineMolecular and Translational Medicineen_US
etd.degree.grantorBoston Universityen_US
dc.identifier.orcid0000-0001-6946-3060


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