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The role of the WWOX tumor suppressor in breast and lung cancer

Iliopoulos, Dmitrio
http://rave.ohiolink.edu/etdc/view?acc_num=osu1155142398

Abstract Details

2006, Doctor of Philosophy, Ohio State University, Molecular, Cellular, and Developmental Biology.
The WWOX gene spans a genomic region of more than half million nucleotide base pairs located at 16q23.3-24.1, a chromosome region commonly involved in LOH in many different types of cancer. Wwox is frequently down-regulated in breast and lung cancers due to DNA hypermethylation in its promoter region. We observed differential patterns of WWOX methylation in neoplastic vs. adjacent non neoplastic tissues, suggesting that targeted WWOX methylation specific amplification could be useful in following treatment or prevention protocols, and WWOX methylation analyses could enrich a panel of DNA methylation markers. Restoration of Wwox expression in Wwox-negative breast and lung cancer-derived cells suppressed tumor growth in vitro and in vivo and induced apoptosis, confirming that WWOX is a tumor suppressor gene that is highly effective in gene therapy of breast and lung cancer xenografts, whether transduced by adenovirus or re-expressed through epigenetic therapy. The preclinical studies that we have performed showed the therapeutic potential of restoration of tumor suppressor expression through epigenetic modulation and the promise of reexpressed tumor suppressors such as WWOX as markers and effectors of the responses. Although many patients benefit from tamoxifen treatment, half of breast tumors that recur after therapy are resistant to tamoxifen. Understanding mechanisms of tamoxifen resistance could lead to characterization of protein markers for identification of nonresponsive cancers, as well as tumors that are acquiring resistance, before emergence of more aggressive cancer cells. We have found that Wwox mediates the tamoxifen response through regulation of protein kinase A and ErbB2 signaling pathways and high Wwox expression level predicted tamoxifen sensitivity in a cohort of breast cancer cases. The results imply that epigenetic reactivation of Wwox could sensitize tamoxifen resistant cells, suggesting possible epigenetic and hormonal combination therapy in patients with acquired tamoxifen resistance.
KAY HUEBNER (Advisor)
159 p.
Biology, Genetics

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Citations

  • Iliopoulos, D. (2006). The role of the WWOX tumor suppressor in breast and lung cancer [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1155142398

    APA Style (7th edition)

  • Iliopoulos, Dmitrio. The role of the WWOX tumor suppressor in breast and lung cancer. 2006. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1155142398.

    MLA Style (8th edition)

  • Iliopoulos, Dmitrio. "The role of the WWOX tumor suppressor in breast and lung cancer." Doctoral dissertation, Ohio State University, 2006. http://rave.ohiolink.edu/etdc/view?acc_num=osu1155142398

    Chicago Manual of Style (17th edition)

osu1155142398
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© 2006, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.