乳癌危險性及年輕化與尿液中鄰苯二甲酸酯類、雙酚A、雌激素受體基因之相關性研究

Association between Urine Phthalate Esters, Bisphenol A, Gene Expression of Estrogen Receptor and Early Onset Breast Cancer

陳柏凱(Bo-Kai Chen)

指導教授 ： 王姿乃

高雄醫學大學/健康科學院/公共衛生學系公共衛生學碩士班/碩士(2016年)

摘要

研究背景：
乳癌為台灣婦女常見的癌症之一。從1973年至2013年，年齡標準化發生率從11.87上升為69.07(每十萬人口)，顯現一個正向成長的趨勢。而台灣的乳癌發生年齡的中位數為45至49歲相較於西方國家年輕了10多歲，有年輕化的趨勢。雌激素受體基因的表現量對於乳癌的病程扮演著重要的角色。許多環境荷爾蒙像是鄰苯二甲酸酯類、雙酚A長久以來被懷疑跟乳癌的發展有關。但部分研究侷限在動物實驗及細胞實驗為主。本研究係利用病例對照研究，觀察早發性乳癌病人、非早發性乳癌病人與社區健康對照的雌激素受體基因ESR1、ESR2、ESRRA、ESRRB等表現量與環境荷爾蒙濃度的分布情形，找出環境荷爾蒙與雌激素受體基因的關係，以及對乳癌的影響。
材料方法：
本研究的個案來自高雄醫學大學附設中和紀念醫院乳房外科，排除良性個案並經由專科醫師診斷為乳癌且願意簽屬人體試驗同意書與問卷訪視之20歲以上患者，並選取高雄地區參加健康檢查之對照，最後選取224位個案以及30位健康對照。以年齡40歲為切點，將病人分為早發性乳癌30人、非早發性乳癌194人，測量尿液中鄰苯二甲酸酯類代謝物以及雙酚A濃度，以及部分受試者血液中雌激素受體基因表現量。所有參與研究之個案，其問卷填答都是經由受過專業訓練之訪視人員進行訪視，問卷內容包含基本人口學資料、職業暴露史、家族史、環境暴露、飲食習慣及過去疾病史等資料。
結果：
經過統計分析檢定結果發現尿液中的鄰苯二甲酸酯類代謝物MIBP、MEHP、Σ4MEHP以及BPA在早發型病患、一般病患以及健康對照中呈現顯著正向的趨勢。早發性乳癌患者尿液中有較高的鄰苯二甲酸酯類代謝物及雙酚A濃度，而社區健康對照尿液中的代謝物濃度最低；再者利用線性回歸分析發現，雌激素受體基因ESR1與鄰苯二甲酸酯類代謝物MEHHP、MECPP、MEOHP、MEHP、以及Σ4MEHP呈現負相關。在校正初經年齡及初胎年齡的邏輯斯模型中，相較於健康對照，病人尿液中前33%濃度的BPA以及MEHP有8.107及6.742倍的風險，而早發型病患之尿液中前33%濃度的MEP，在校正初經年齡、初胎年齡、PR以及Her2模型中，相較於非早發性乳癌患者，早發性患者有3.205倍的風險。
結論：
本研究發現尿液中鄰苯二甲酸酯類與雙酚A的濃度在早發型病患中最高、非早發病患次之、健康對照最低；儘管在三組中沒有達到顯著差異，但整體來看依舊呈現一個遞減的趨勢。且部分鄰苯二甲酸酯類代謝物對於乳癌的風險、早發型乳癌的風險都有顯著意義。另外也發現環境荷爾蒙的濃度與ESR1基因表現量呈現負相關，推測體內基因表現量，可能會因為暴露於環境荷爾蒙的多寡造成影響。

關鍵字

乳癌 ； 鄰苯二甲酸酯類 ； 雙酚A ； 雌激素受體

並列摘要

INTRODUCTIONS:
Breast cancer is one of the most common diseases in women. The standard incidence rate has been growing for over thirty years. The median age of onset in breast cancer patients of Taiwan is 45 to 49. Compared to other western countries, there is a younger trend in Taiwan. The gene expression of estrogen receptor plays an important role in breast cancer pathogenesis. Environmental hormones such as phthalate esters and bisphenol A, had been suspected that they had estrogen effects. The aims of present study is to explore the relationship between the environmental hormones, gene expression of estrogen receptor and breast cancer by a case-control study.
MATERIALS AND METHODS:
Breast cancer patients of present study were recruited from Kaohsiung Medical University Hospital and health controls were recruited from communities in Kaohsiung. They were willing participate the study and sign the informed consent and the age is more than twenty years old. Cases were diagnosed by physicians, and were confirmed by the pathological lesion examination. We excluded the patients with benign breast disorder having cancer before. We included 224 cases and 30 health controls. We categorized the cases according to the diagnosis age of 40 into two groups of early onset and non-early onset patients. Finally, we measured the phthalate metabolites and bisphenol A concentrations in urine and gene expression levels of estrogen receptor.
RESULTS:
The present study found that early onset patients have the highest levels of phthalate metabolites and bisphenol A in urine. Although the statistical analysis didn’t show a significant difference, but the results showed that the descending trend was significant. The regression analysis found that gene expression of estrogen receptor is negatively related to some phthalate metabolites. We used the cut point of upper tertile concentration of phthalate metabolite and bisphenol A. We found that the odds ratio of MEHP and BPA are 6.7 and 8.1 for breast cancer, respectively. The odds ratio of early onset is 3.2 in urine after adjust for the confounders.
CONCLUSIONS:
The present study found that phthalate esters and bisphenol A exposure may increase the risk of breast cancer and even the early onset breast cancer. Phthalate esters and bisphenol A may regulate gene expression of estrogen receptor and influence the pathogenesis of breast cancer. But the mechanism is needed to clarify in further studies.

並列關鍵字

breast cancer, phthalate, bisphenol A, gene expression

參考文獻

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