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This dissertation, Identification of MicroRNAs Associated With Tamoxifen Resistance in Breast Cancer by Lai-yee, Lau, 劉麗儀, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: Tamoxifen is the most widely used endocrine therapy for both early and advanced estrogen receptor (ER) positive breast cancer patients. About half of the patients that initially respond to the antiestrogen become estrogen-independent and ultimately develop resistance to the treatment. The precise molecular mechanisms of tamoxifen resistance remain poorly understood. Dysregulation of microRNAs (miRNAs) has been frequently reported in breast cancer and linked to cancer development, progression and therapeutic response. To gain a more comprehensive picture of the miRNA regulatory network for modulating tamoxifen responsiveness, we examined global expression profiles of more than 600 miRNAs in a matched pair of tamoxifen-sensitive ZR75 and tamoxifen-resistant AK47 breast cancer cell lines using TaqMan Low Density Array (Applied Biosystems). Under 4-hydroxytamoxifen treatment, 102 miRNAs displayed differential responses between the sensitive cells and the resistant cells. At basal levels, upregulation of 32 miRNAs and downregulation of 75 miRNAs were observed in the resistant cells as compared to the sensitive cells. Among the 9 miRNAs of significant differential expression selected for validation, expression profiles of the 7 miRNAs could be reproduced. Of these, 4-hydroxytamoxifen treatment greatly increased miR-449a/b expression in sensitive ZR75 cells, whereas miR-449a/b expression was significantly reduced in resistant AK47 cells at basal levels, which was further confirmed in a panel of tamoxifen-resistant breast cancer cell lines. Such downregulation of miR-449a/b in the resistant cells was partially attributed to DNA methylation-mediated repression of miR-449a/b. Notably, miR-449a/b expression exhibited a significant positive correlation with ER-α status (miR-449a: P=0.006, miR-449b: P=0.013) and progesterone receptor (PR) status (miR-449a: P=0.010, miR-449b: P=0.021), and a prominent inverse association with tumor grade in 61 breast cancer tissues (miR-449a: P=0.001; miR-449b: P=0.009). Also, breast cancer patients with high miR-449a/b expression tended to have increased disease-free survival (miR-449a: P=0.019; miR-449b: P=0.117). To further support the tumor suppressor function of miR-449, stable miR-449b overexpression in the resistant cells reduced cell proliferation. More intriguingly, restoring miR-449b expression increased sensitivity to 4-hydroxytamoxifen-induced apoptosis via suppression of AKT activity without restoring ER-α expression. In contrast, miR-449a/b knockdown reduced ER-α and PR expression, but enhanced phosphorylation of AKT, extracellular signal-regulated kinase- 1/2 (ERK1/2), c-Jun N-terminal kinases (JNK) and also ER-α at serine 167 and serine 118 residues. Furthermore, we demonstrated c-Myc is a target gene of miR-449 as confirmed by bioinformatics and experimental analyses. Computational algorithms predicted a highly conserved miR-449a/b binding site within C-MYC 3'untranslated region (3'UTR). Compared to the parental sensitive cells, c-Myc was overexpressed in the resistant cells. Forced expression of miR-449b suppressed c-Myc protein level. To further support the notion that c-Myc is a direct target of miR-449, interactions between miR-449b and C-MYC 3'UTR were confirmed by co-expression of miR-449b and c-Myc expression constructs and luciferase reporter assay. Taken together, our data strongly sugg

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