乳癌是全世界婦女中最常見的癌症，也是婦女因癌症死亡最主要的原因。越來越多的研究表明乳癌是由基因、表觀遺傳基因和環境因素引起的。表觀遺傳調控在乳癌生物學中逐漸受到重視。我們藉由大數據探勘的方法來建立人類細胞的候選基因和表觀遺傳基因網路(GEN)。我們根據正常乳房細胞和乳癌細胞的次世代定序數據(NGS數據)，並藉由系統識別和系統階層測定方法來刪減候選GEN中的偽陽性並獲得四期乳癌的全基因組GEN。接著，為了研究重要的分子機制，我們藉由主成份網路投影方法(PNP)從各期的GEN萃取出對應的核心GEN。為了分析乳癌的發展機制，我們比較連續兩期乳癌的核心GEN並進一步萃取出核心生物途徑來找出差異的生物途徑並挑選出乳癌發展機制中的關鍵基因和表觀遺傳基因生物標誌物。此外，我們也確定了表觀遺傳調控和微環境因素在乳癌發展機制中的作用。這些重要的發展機制以及表觀遺傳調控的改變顯示，早期乳癌細胞比起正常細胞有較高的增生能力並促進腫瘤附近的淋巴管形成。淋巴管附近的中期乳癌細胞有趨化性移動的傾向並與淋巴內皮細胞的膜蛋白結合而促進淋巴轉移。晚期乳癌細胞受到巨噬細胞分泌因子的刺激以及上皮間質轉換(EMT)的影響使其細胞黏附能力被抑制。根據這些發展機制，我們識別了數個促進乳癌發展的基因和表觀遺傳基因生物標誌物作為藥物目標。最後，我們提出三組多重藥物針對這些基因和表觀遺傳基因生物標誌物來治療其對應的各期乳癌。

Breast cancer is the most common cancer and also the major cause of death by cancer among women throughout the world. Accumulating studies indicate that breast cancer is caused by complex combination of genetic, epigenetic and environmental factors. Epigenetic regulation recently has become an increasingly important aspect of breast cancer biology. We constructed the candidate genetic and epigenetic network (GEN) of human cells by using big database mining. Based on next generation sequencing data (NGS data) of breast normal and cancer cells, we identified four genome-wide GENs of each stage of breast cancer by pruning false-positives in candidate GENs through system identification method and system order detection scheme. Then, in order to investigate the significant molecular mechanisms, we extracted the corresponding core GENs from their GENs in each stage via principal network projection (PNP) method. To analyze the progression mechanisms of breast cancer more conveniently, we further extracted the core pathways by comparing two core GENs of two consecutive stages of breast cancer to find differential pathways and choosing the most crucial genetic and epigenetic biomarkers playing the key roles on the progression mechanisms in breast carcinogenesis. In addition, we also identified the roles of identified epigenetic regulations and microenvironment factors in the progression mechanism of breast cancer in their interacting with these core pathways. According to these key progression mechanisms, early-stage breast cancer cells have a higher ability of cell proliferation than normal cells to promote lymphangiogenesis around tumor resulting from the change of related epigenetic regulations. Mid-stage breast cancer cells around lymphatic vessels tend to chemotactic migration and binding to the membrane proteins of lymphatic endothelial cells to promote lymphatic metastasis due to the change of related epigenetic regulations. Late-stage breast cancer cells are stimulated by the factors secreted from macrophages and affected by epithelial-mesenchymal transition (EMT), and their cell adhesion ability is also inhibited due to the change of related epigenetic regulations. Based on these progression mechanisms, we identified several genetic and epigenetic biomarkers crucial to promote breast carcinogenesis as drug targets. Finally, we proposed three multiple drugs to target these genetic and epigenetic biomarkers for therapeutic treatment of breast cancer at three corresponding carcinogenic stages.

誌謝 I
摘要 II
Abstract IV
List of Tables VIII
List of Figures IX
Chapter 1. Introduction 1
Chapter 2. Materials and Methods 4
2.1 Big data mining to construct genome-wide candidate GEN 5
2.2 Constructing the systematic models for the GENs 5
2.3 Parameter estimation of the system models of candidate GEN via system identification method and NGS data 9
2.4 Extracting the core GENs from the GENs by PNP method 17
Chapter 3. Results 21
3.1 The identified GENs, core GENs and their corresponding core pathways in each stage of breast cancer cells 21
3.2 Differential core pathways from normal to early-stage breast cancer cells 22
3.3 Differential core pathways from early-stage to mid-stage breast cancer cells 24
3.4 Differential core pathways from mid-stage to late-stage breast cancer cells 26
Chapter 4. Discussion 29
4.1 Progression genetic and epigenetic mechanisms from normal cells to early-stage breast cancer cells 29
4.2 Progression genetic and epigenetic mechanisms from early-stage to mid-stage breast cancer cells 32
4.3 Progression genetic and epigenetic mechanisms from mid-stage to late-stage breast cancer cells 34
4.4 Multiple drugs design for each stages of breast cancer by integrating progression genetic and epigenetic mechanisms with drug databases 37
Chapter 5. Conclusion 42
Tables 44
Figures 48
Reference 62

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