乳癌為台灣女性最好發的癌症，而侵襲性乳腺癌是最常見的乳癌。越來越多的研究顯示癌症幹細胞與腫瘤發生、腫瘤進展及抗藥性有關。而癌症幹細胞的形成與誘導多潛能性幹細胞的重新引導因子:Octamer-binding Protein 4 (Oct4) 、Sex-determining Region Y (SRY)-related Box 2 (Sox2) 、 Nanog 及Lin28的表現有關。本研究目的在於探討能誘導多潛能性幹細胞之重新引導因子:Oct4、Sox2、Nanog、Lin28的蛋白質表現量與侵襲性乳腺癌發生的關係以及與這些癌患的臨床病理特性及其預後的相關性。本研究將309個侵襲性乳腺癌與20個乳房纖維化囊腫病人的石蠟包埋檢體製作成組織晶片，並利用組織免疫染色法檢測Oct4、Sox2、Nanog、Lin28蛋白質表現量於正常乳腺組織、腫瘤鄰近正常乳腺組織、乳管原位癌、侵襲性乳腺癌及癌復發組織之表現量。我們的組織免疫染色法檢測結果顯示，Sox2 與Lin28表現於半數癌患的腫瘤組織中，陽性率分別為49.6%和49.7%，而Oct4和Nanog較少表現，陽性率分別為13.5%和24.7%。這4個蛋白質表現量彼此呈正相關，此外，這4個蛋白質在腫瘤鄰近正常乳腺組織的表現量比乳房纖維化囊腫病人的正常乳腺組織來的高。然而比較侵襲性乳腺癌患者的不同組織如:腫瘤鄰近正常乳腺、乳管原位癌、侵襲性乳腺癌與再發組織的4個蛋白質表現量，隨著腫瘤的發生與進展其蛋白質表現量逐漸下降。但比較侵襲性乳腺癌與再發組織中此4個蛋白質的表現量並無明顯差異。此4個蛋白質的表現量高與兩個好的臨床病理特性及一個乳癌生物標記有關，例如:細胞核表現Sox2與Lin28在病理分期第一期的病人的腫瘤組織中表現量較高;細胞核表現此4個蛋白質在細胞分化良好或中等的病人中的表現量較高;Sox2蛋白質在雌激素受體陽性的病人中表現量較高。然而，此4個蛋白質表現量與侵襲性乳腺癌患者之存活有任何關係。綜合而論，在侵襲性乳腺癌腫瘤的形成當中，這4個蛋白質在腫瘤發生中可能扮演重要的角色，但在腫瘤進展中的角色就不那麼重要。

Breast cancer is the most common cancer in Taiwanese women and the invasive ductal carcinoma (IDC) is the most common type. Increasing evidence shows that cancer stem cells (CSCs) have been implicated in tumorigenesis, tumor progression, and drug-resistance. In addition, four reprogramming factors (Octamer-binding Protein 4 (Oct4), Sex-determining Region Y (SRY)-related Box 2 (Sox2), Nanog and Lin28) employed to induce induced pluripotent stem (iPS) cells are associated with CSCs formation. The purpose of this study was to investigate the relationship of the protein expression levels of the reprogramming factors (Oct4, Sox2, Nanog and Lin28) with the tumorigenesis, clinicopathologic outcomes and prognosis of breast IDC patients. Immunohistochemistry (IHC) assay of tissue microarrays, made by 309 IDC and 20 breast fibrosis paraffin embedded samples, were used to examine the protein expression levels of Oct4, Sox2, Nanog and Lin28 in normal mammary ductal tissues, tumor adjacent normal mammary ductal tissues, ductal carcinoma in situ (DCIS), IDC and recurrence tissues. Our IHC results showed that Sox2 and Lin28 were expressed in half of breast IDC patients’ tumor tissue (49.6% and 49.7%, respectively), but Oct4 and Nanog are less expressed (13.5% and 24.7%, respectively). The protein expression levels of the four proteins were positively correlated with each other. In addition, the expression levels of the four proteins were upregulated in tumor adjacent normal tissue as compared to breast fibrosis pateints’ normal mammary ductal tissue. To compare the expression levels of the four proteins in different tissues; such as tumor adjacent normal, DCIS, IDC and recurrence tissues, the expression levels of the four protiens gradually decreased when tumor developed and progressed. However, their expression levels were comparable between IDC and recurrence tissues. Additionally, the high expression levels of four proteins were high in two good clinicopathological characteristics and a biomarker of breast cancer; such as nuclear Sox2 and Lin28 in those with pathology stage I; nucleus expression of the four proteins in those with well and moderate cell differentiation; and Sox2 in those with positive estrogen receptor. However, the four proteins’ expression levels were not correlated with IDC patients’ survival. In conclusion, the reprogramming factors: Oct4, Sox2, Nanog and Lin28 may play an important role in tumorigenesis of breast IDC, but their impacts on tumor progression were quite small.

Abbreviations ------------------------------------------------------------4
Abstract in Chinese ----------------------------------------------------6
Abstract in English -----------------------------------------------------8
Contents ----------------------------------------------------------------10
Introduction
1. Epidemiology and molecular subtypes of breast cancer --------------------------------------------------------------------12
2. Breast Gland Development and stem cells ------------------------------------------------------------------------------13
3. Stem cells, cancer stem cells (CSCs) and induced pluripotent stem (iPS) cells---------------------------------14
Octamer-binding Protein 4 (Oct4) ---------------------15
Sex-determining Region Y (SRY)-related Box 2(Sox2) ----------------------16
Nanog--------------------------------------------------------------------17
Lin28----------------------------------------------------------------------18
Specific Aims ----------------------------------------------------------20
Subjects and Methods ----------------------------------------------21
Results
1. Breast cancer intrinsic subtypes and clinicopathological parameters-----------------------------------27
2. Expression levels of reprogramming factors in normal ductal epithelial tissue,tumor-adjacent normal ductal epithelial tissue, tumor and recurrence tissue ---------------28
3. Association between the expression level of Oct4 in tumor and demographic,clinicopathological parameters and survival -------------------------------------------------------------31
4. Association between the expression level of Sox2 and demographic, clinicopathological parameters and survival ------------------------------------------------------------------------------32
5. Association between the expression level of Nanog and demographic, clinicopathological parameters and survival ------------------------------------------------------------------------------33
6. Association between the expression level of Nanog and demographic, clinicopathological parameters and survival ------------------------------------------------------------------------------34
7. Association of DSS and DFS between reprogramming factors’ protein expression in tumor and breast cancer intrinsic subtypes and adjuvant therapy status -----------------------------------------------------------------------------35
Discussion -------------------------------------------------------------36
Conclusioin ------------------------------------------------------------39
References -------------------------------------------------------------41
Tables --------------------------------------------------------------------49
Figures ------------------------------------------------------------------70
Index ----------------------------------------------------------------------81

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