dc.contributor.advisor | Jensen, Roy A | en_US |
dc.contributor.advisor | Behbod, Fariba | en_US |
dc.contributor.author | Stecklein, Shane Richard | |
dc.date.accessioned | 2012-07-22T18:02:41Z | |
dc.date.available | 2012-07-22T18:02:41Z | |
dc.date.issued | 2012-05-12 | en_US |
dc.date.submitted | 2012 | en_US |
dc.identifier.other | http://dissertations.umi.com/ku:12058 | en_US |
dc.identifier.uri | http://hdl.handle.net/1808/9982 | en_US |
dc.description.abstract | Expression of functional breast cancer susceptibility gene 1 (BRCA1) in human cancers is associated with resistance to platinum-based chemotherapeutics and poly(ADP-ribose) polymerase (PARP) inhibitors. BRCA1 is a nuclear phosphoprotein with broad tumor suppressor activities that, among other functions, is critical for resolving double-strand DNA breaks (DSBs) and interstrand crosslinks (ICLs) by homologous recombination (HR). In vitro, animal and human clinical data have demonstrated that BRCA1-deficient cancers are highly sensitive to ICL-inducing alkylative chemotherapeutic agents, are amenable to synthetic lethal approaches which exploit defects in DSB/ICL repair (e.g., PARP inhibitors), and are generally associated with more favorable responses to anti-neoplastic therapy and improved survival. Conversely, high expression of wild-type BRCA1 in a number of cancers, as well as frame-restoring intragenic mutations in BRCA1 mutant ovarian cancers, is associated with therapeutic resistance and poor prognosis. Accordingly, there has been much interest in identifying, exploiting and manipulating DSB/ICL repair capacity to restore or enhance sensitivity to cancer therapeutics. In this study, we demonstrate that the heat shock protein 90 (HSP90) inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG (Tanespimycin)), which is currently in Phase II/III clinical evaluation, induces BRCA1 ubiquitination and proteasomal degradation in numerous in vitro models. Mechanistically, we show that loss of HSP90 function completely abolishes both homologous recombination and non-homologous end joining of DSBs, that BRCA1-deficient cells are hypersensitive to 17-AAG due to enhanced replication stress and aberrant entry into mitosis, and that 17-AAG can reverse BRCA1-dependent repair-mediated resistance. Additionally, we assessed the role of BRCA1 promoter methylation in sporadic triple-negative breast cancers (TNBCs) and identify a novel biomarker for poor response to anthracycline regimens in human patients. In summary, we document a novel upstream HSP90-dependent regulatory point in the Fanconi anemia/BRCA DSB/ICL repair pathway, illuminate the role of BRCA1 in regulating damage-associated checkpoint and replication responses to HSP90 inhibitors, specifically identify BRCA1 as a novel, clinically relevant target for enhancing radio- and chemosensitivity in refractory and/or resistant malignancies, and identify a useful biomarker for studies of therapeutic sensitivity in human TNBCs. | |
dc.format.extent | 230 pages | en_US |
dc.language.iso | en_US | en_US |
dc.publisher | University of Kansas | en_US |
dc.rights | This item is protected by copyright and unless otherwise specified the copyright of this thesis/dissertation is held by the author. | en_US |
dc.subject | Cellular biology | |
dc.subject | Oncology | |
dc.subject | Pathology | |
dc.subject | Brca1 | |
dc.subject | Breast cancer | |
dc.subject | Chemosensitivity | |
dc.subject | Dna repair | |
dc.subject | Double-strand break | |
dc.subject | Ovarian cancer | |
dc.title | Identification, Exploitation and Manipulation of BRCA1-Dependent DNA Double-Strand Break and Interstrand Crosslink Repair in Breast and Ovarian Cancer Therapy | |
dc.type | Dissertation | en_US |
dc.contributor.cmtemember | Fields, Timothy A | |
dc.contributor.cmtemember | Fan, Fang | |
dc.contributor.cmtemember | Cheng, Nikki | |
dc.contributor.cmtemember | Neufeld, Kristi L | |
dc.thesis.degreeDiscipline | Pathology & Laboratory Medicine | |
dc.thesis.degreeLevel | Ph.D. | |
kusw.oastatus | na | |
kusw.oapolicy | This item does not meet KU Open Access policy criteria. | |
kusw.bibid | 8085716 | |
dc.rights.accessrights | openAccess | en_US |