台灣乳癌病人瘦激素及瘦激素受體基因多型性與血脂肪及腫瘤轉移及復發相關性之探討

The study of relationship between leptin and leptin receptor gene polymorphisms and lipid and prognosis in Taiwanese patients with breast cancer

饒秀芬(Hsiu-Fen Jao)

指導教授 ： 蔡麗玉

高雄醫學大學/健康科學院/生物醫學檢驗學研究所/碩士(2008年)

摘要

根據行政院衛生署的統計，國人十大死因二十幾年來皆由惡性腫瘤蟬連榜首，在女性方面乳癌則為十大癌症死因中的第四位且其發生率由民國91年的第二位躍升為民國92年的第一位。由於生活水準的提升及飲食西化，再加上生活壓力及缺乏運動的結果，導致國人肥胖的比例上升。而與肥胖相關的疾病很多，乳癌就是其中之一。根據研究，在停經後的婦女當中，肥胖是罹患乳癌的一個危險因子，但此機轉至今仍未有定論。此外根據統計肥胖的乳癌患者其預後也較差。瘦激素是一種由脂肪組織所合成及分泌的一種似荷爾蒙調控因子，會作用在下視丘來調控飲食及能量的消耗。瘦激素在體內要發揮功用必須與瘦激素受體結合才能進行，在臨床研究發現過度肥胖者其體內瘦激素含量有增加的情形，主要是因為瘦激素受體無法發揮作用而產生瘦激素阻抗現象（leptin resistance）。在乳癌組織中當瘦激素與受體結合後會經由JAK2及STAT3訊息傳遞路徑促使癌細胞的增生及存活。此外也會提升芳香環轉化酶（Aromatase）的活性，進而使得雌激素（estrogen）上升，並抑制雌激素瘦體的分解（proteasomal degradation of ERα），因此罹患乳癌的危險也隨之增加。根據研究指出，位於瘦激素轉譯起始點（leptin start codon）上游2548 b.p的基因多型性（G-2548A），與脂肪組織瘦激素的產量有關（AA genotype產量較高）。而瘦激素瘦體（leptin receptor）第223個胺基酸的變異（Q223R）則與受體的親合力有關（RR genotype親合力較高）。故本實驗的目的在研究瘦激素及瘦激素瘦體的基因多型性是否與乳癌罹患率、預後及血清脂蛋白含量有相關性存在。
結果：根據本實驗，我們發現此兩種基因多型性與台灣婦女罹患乳癌的危險性無關，但乳癌患者為Leptin receptor RR者，其腫瘤大小比QR的患者有較小的趨勢；Leptin（G-2548A）為A carrier時，其腫瘤復發或轉移的機率是較小的。此外本實驗結果也顯示在台灣婦女當中，較低的高密度脂蛋白（HDL-C）及較高的T-CHOL/HDL-C、LDL-C/HDL-C是罹患乳癌的風險因子，且在停經後的婦女當中，較高的身體質量指數（BMI）也是罹患乳癌的風險因子。
結論：經由基因多型性的篩選來預期乳癌病人的腫瘤大小、復發及轉移機率對臨床來說是可行的。

關鍵字

瘦激素 ； 瘦激素受體

並列摘要

According to the statistics revealed by the Department of Health, Executive Yuan, R.O.C (Taiwan), malignant tumor is the leading causes of death in Taiwan for the lastest 20 years. In female, breast cancer is the fourth cause of death in top 10 cancers, and the incidence rate rised to No. 1 in 2003. As a result of change of diet hobby, exercise, and augmentation of life pressure, the obesity rate is rise in Taiwan. There are many diseases relate to obesity, and breast cancer is one of them. According to the previous study, obesity is a risk factor for breast cancer in postmenopausal women, but the reason is still not clear. Additionally, an obese breast cancer patient who’s prognosis is poor. Leptin is a kind of hormone synthesized and secreted by adipose tissue, acts as a neurohormone-regulating energy balance and food intake in the hypothalamus. Leptin exerts its physiological action via the leptin receptor. Clinically, obese humans have increased circulating levels of leptin , suggest that obesity may be related to a leptin-resistant state. In breast cancer tissue, when leptin ligand to leptin receptor, it will promote cancer cell proliferation and survival by JAK2 and STAT3 pathway, increase activity of aromatase, inhibit proteasomal degradation of ERα. Enhanced gene expression and increased circulating leptin levels have been reported in those with the Leptin (-2548AA) genotypes, and enhanced leptin binding activity been reported in those with the leptin receptor (223RR) genotypes. The aim of this study is to identify the relationship between leptin and leptin receptor gene polymorphisms and lipid and prognosis in Taiwanese patients with breast cancer.
There was no evidence for a strong association between genotypes and risk of breast cancer and lipoproteins. But patients with LEPR 223RR, will have smaller tumor than LEPR Q carriers, patients with LEP A allele will have lower metastasis rate. Furthermore, our results indicated that low HDL-C, high T-CHOL, T-CHOL/HDL-C, and LDL-C/HDL-C and BMI were risk factors for breast cancer in Taiwan.

並列關鍵字

leptin ； leptin receptor

參考文獻

政院衛生署網站 http://www.bhp.doh.gov.tw/

American Cancer Society website http://www.cancer.org/

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