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BAF57 MODULATION OF ANDROGEN RECEPTOR ACTION AND PROSTATE CANCER PROGRESSION

LINK, KEVIN A
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1198854849

Abstract Details

2008, PhD, University of Cincinnati, Medicine : Cell and Molecular Biology.
Prostate cancer relies on androgens for growth and survival. Androgens elicit their function primarily through the androgen receptor (AR), a transcription factor that is required for the development and progression of prostate cancer. Therefore, current treatment options for disseminated disease are aimed at either inhibiting androgen synthesis or preventing activation of the receptor. These treatment options are initially effective; however, recurrent disease ultimately arises within two to three years that typically present as therapy resistant. From this, it is obvious that more effective means of targeting this pathway are necessary to treat prostate cancer. The present study exploited a specific aspect of the AR activation pathway and uncovered a novel means for potentially targeting AR action and subsequent prostate cancer proliferation. The SWI/SNF chromatin remodeling complex is one such necessary component involved in mediating AR activation. Specifically, the BRM core ATPase was demonstrated to exhibit a preferential response to activating AR target genes which was dependent on promoter context. Subsequent studies identified the BAF57 subunit of the SWI/SNF complex as the primary interacting AR subunit, thus indicating a possible role in complex recruitment to AR target DNA. BAF57 proved to be critical for AR mediated transcriptional activation, AR enhanced coactivator activation, and prostate cancer proliferation. Based on these findings, the potential for targeting BAF57 as a prostate cancer therapeutic option was examined. First, expression of BAF57 was verified in human prostate tissue specimens, with possible enhanced expression observed in metastatic samples. Subsequent molecular analyses determined that the primary region of interaction occurred between the DBD/hinge region of AR and the proline-rich/HMG domain of BAF57. The N-terminal binding region of BAF57 was then shown to reduce AR recruitment to AR target genes, inhibit AR target gene activity, and decrease prostate cancer cell proliferation. Together, the data herein establish the SWI/SNF chromatin remodeling complex, specifically BAF57, as a valid target for the treatment of prostate cancer.
Dr. Karen Knudsen (Advisor)
158 p.
Biology, Molecular
prostate cancer; androgen receptor; BAF57; SWI/SNF

Recommended Citations

Citations

  • LINK, K. A. (2008). BAF57 MODULATION OF ANDROGEN RECEPTOR ACTION AND PROSTATE CANCER PROGRESSION [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1198854849

    APA Style (7th edition)

  • LINK, KEVIN. BAF57 MODULATION OF ANDROGEN RECEPTOR ACTION AND PROSTATE CANCER PROGRESSION. 2008. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1198854849.

    MLA Style (8th edition)

  • LINK, KEVIN. "BAF57 MODULATION OF ANDROGEN RECEPTOR ACTION AND PROSTATE CANCER PROGRESSION." Doctoral dissertation, University of Cincinnati, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1198854849

    Chicago Manual of Style (17th edition)

ucin1198854849
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© 2007, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.