乳癌是全世界女性最常見的惡性腫瘤之一，也是癌症致死的重要原因。依據世界衛生組織統計，北美、澳洲、西歐與北歐的乳癌發病率及死亡率高，而亞洲國家，包括台灣，發病率則低。但台灣地區乳癌的發病率近年來明顯上升，且發病高峰年齡比歐美國家提前十歲，顯示基因或環境因素導致臨床表徵上之差異。1896年，Beatson發現停經前婦女接受雙側卵巢切除術後乳癌病徵因此減緩，暗示類固醇荷爾蒙是乳癌的關鍵因素。在雌激素的效應下，雌激素受體在乳癌的生理發育扮演重要角色。雌激素受體蛋白屬固醇類核受體超家族成員之一，是由雌激素活化的轉錄因子。雌激素受體蛋白有兩個顯型-a與b。在正常乳房組織中，雌激素受體-a侷限於腺管與小葉的上皮細胞，這些細胞與乳癌癌化的主要細胞同源，因此a型雌激素受體在乳癌發生過程中極為重要。本研究主要是探討雌激素受體-a基因變異與乳癌的相關性。雌激素受體-a位於第6對染色體q25.1，包含8個外顯子，蛋白上包括荷爾蒙活化區、DNA結合區與轉錄激活區。雌激素受體-a基因突變和單一核苷酸基因多型性在高加索人種的研究資料多，而亞洲地區則付之闕如。在此研究，我們探討台灣雌激素受體-a基因突變的變異與其臨床意義。我們採集了來自國立成功大學附設醫院與行政院衛生署台南醫院的189名乳癌病人和177名正常對照組。病例和對照組的年齡分佈相近。用與聚合酶連鎖反應結合的單鏈構象多型性分析和定序作初步篩檢的工具。我們結果顯示台灣地區存在三個多型性位點：外顯子-1上的密碼子-10（TCT/TCC）、外顯子-4上的密碼子-325（CCC/CCG）、外顯子-8上的密碼子-594（ACG/ACA）。接著設計以融解曲線分析的專一位點之即時性聚合酶連鎖反應，完成進一歩分析。我們的結果發現雌激素受體-a基因的密碼子-10處，基因型頻率（Ｐ=0.026）與等位頻率（Ｐ=0.018）在乳癌病人和正常對照組有顯著的不同。在家族史的乳癌中，雌激素受體-a基因的密碼子-594處異合型594 ACG/ACＡ比同合型ACG/ACG，會有較低的危險性罹患家族性乳癌。密碼子-594處G等位基因會降低在早期發病的危險性。另外雌激素受體-a基因的密碼子-325和594多型性位點與淋巴結轉移相關，獨立或協力可作為預測乳癌病患是否發生淋巴轉移之生物標的。本研究首度顯示台灣地區雌激素受體-a基因多型性，與其乳癌的臨床相關性。

Breast cancer, one of the most common malignancies diagnosed in women worldwide, is the leading cause of cancer-related death. According the World Health Organization survey, North America, Australia, Western Europe and Northern Europe have high incidence and mortality rates from breast cancer. In 1896, Beatson observed that premenopausal breast-cancer patients resulted in remission of their disease after bilateral oophorectomy, which implicated steroid hormones being a major determinant of breast cancer. Estrogen receptor (ER) has important roles in modulating the effect of estrogen on development and growth of breast cancer. The human ER protein, a member of steroid nuclear receptor superfamily, is a ligand-activated transcription factor. The human ER protein consists two types, namely a and b. ERa expression is restricted to epithelial cells lining within ducts and lobules, where the most breast cancers come from. Therefore, our study aimed on the relationship between ERa and breast cancer. The ERa gene is located at chromosome 6q25.1, composed of eight exons, including regions important for hormone binding, DNA binding, and activation of transcription. The mutation and single nucleotide polymorphisms（SNP）sites have not been explored in Taiwan, an area with low incidence for breast cancer than in Western countries. In this study, we analyze the mutation and SNPs sites along with the ERa coding region, in search of linkage to clinical courses of breast cancer in Taiwanese population. We recruited 189 breast cancer patients and 177 normal controls from National Cheng Kung University Hospital and Tainan General Hospital, Department of Health, Taiwan, R.O.C. Cases and controls were matched by age. A polymerase chain reaction combined with single-strand conformation polymorphism (PCR-SSCP) and sequencing was exploited as an initial screening approach. Our study revealed three SNPs sites in exon 1 (codon 10, TCT/TCC), exon 4 (codon 325, CCC/CCG) and exon 8 (codon594, ACG/ACA). Subsequently, a site-specific real-time PCR in couple with melting curve analysis was designed for high-through assay. Our data showed that the genotypic (P=0.026) and allelic frequencies (P=0.018) of the ERa gene codon 10 polymorphism were significantly different between the breast cancer and control groups. Regarding family history of breast cancer, the codon 594 ACG/ACG revealed an increased risk. Furthermore, codon 594 G allele reduced a risk of early onset age. Notably, the ERa gene codon 325 and 594 polymorphisms had a reverse association with lymph node metastasis in a synergistic mode. This study first showed ERa gene polymorphisms in Taiwan, with the clinical relevance of breast cancer.

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