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dc.contributor.advisor Marks, Jeffrey R en_US
dc.contributor.author Horne, Hisani en_US
dc.date.accessioned 2010-05-10T19:56:21Z
dc.date.available 2012-05-01T04:30:04Z
dc.date.issued 2010 en_US
dc.identifier.uri http://hdl.handle.net/10161/2376
dc.description Dissertation en_US
dc.description.abstract <p>MAL (myelin and lymphocyte protein), has been implicated in several malignancies including esophageal, gastric, and cervical cancers. We have demonstrated that the MAL protein is expressed in the normal breast epithelium, and aberrantly expressed in breast cancer. Bisulfite sequencing of the MAL promoter CpG island revealed hypermethylation in breast cancer cell lines and 69% of primary tumors analyzed compared with normal breast epithelial cells. Differential methylation between normal and cancer DNA was confined to the proximal promoter region. In a subset of breast cancer cell lines, promoter methylation correlated with transcriptional silencing that was reversible with the methylation inhibitor decitabine. Furthermore, exogenous expression of MAL in breast cancer cell lines resulted in decreased cell proliferation, motility, reduced cell invasion through Matrigel and suppressed anchorage-independent growth in soft agar. In a cohort of 122 primary breast tumors, immunohistochemical analysis revealed that the MAL protein was an independent predictor of benefit from adjuvant chemotherapy. Moreover, overexpression of MAL in triple-negative MDA-MB-468 and BT20 breast cancer cell lines was sufficient to confer sensitivity to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibition and was associated with reduced phosphatidylinositol-3 kinase (PI3K)/Akt signaling. Immunohistochemistry studies conducted on 144 late-stage serous ovarian cancers showed that MAL expression was a significant predictor of survival. Knockdown of MAL expression in the SKOV8 ovarian cancer cell line reduced cell proliferation and resulted in increased sensitivity to the chemotherapeutic drug carboplatin. Thus, we have identified the MAL gene as a novel epigenetically regulated gene in breast cancer with implications for response to chemotherapy in both breast and ovarian cancer. Furthermore, we have shown that the MAL protein has predictive and prognostic value in breast and ovarian cancers, respectively.</p> en_US
dc.format.extent 48016931 bytes
dc.format.mimetype application/pdf
dc.language.iso en_US
dc.subject Biology, Molecular en_US
dc.subject Health Sciences, Oncology en_US
dc.subject Breast-Cancer en_US
dc.subject hypermethylation en_US
dc.subject myelin and lymphocyte protein en_US
dc.subject ovarian cancer en_US
dc.title The Role of the Myelin and Lymphocyte Protein (MAL) in Breast and Ovarian Cancer en_US
dc.type Dissertation en_US
dc.department Pathology en_US
duke.embargo.months 24 en_US

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