Aromatase and breast cancer susceptibility
Aromatase and breast cancer susceptibility
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DOI：
10.1677/erc.0.0060165
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发表时间：
1999-06-01
影响因子：
3.9
通讯作者：
Henderson, BE
中科院分区：
文献类型：
--
作者：
Probst-Hensch, NM;Ingles, SA;Henderson, BE
基于实验和流行病学证据，假设雌激素通过增加乳腺上皮细胞的有丝分裂活性来增加乳腺癌的风险。芳香化酶对雌激素的生物合成至关重要，因此可能在乳腺癌的发展中发挥作用。支持芳香化酶在乳腺肿瘤生物学中的病因学作用的数据是几倍。首先，体重与绝经后乳腺癌风险之间的关联可能是由芳香酶介导的。其次，一项初步研究发现，与健康女性相比，乳腺癌病例的正常乳腺脂肪组织中芳香化酶表达更高。第三，动物实验数据表明，芳香化酶活性使乳腺组织易发生癌前病变和肿瘤病变。在洛杉矶和夏威夷进行的一项多种族队列研究中，我们调查了（i）不同种族人群的血浆雌酮与雄烯二酮（E1/A）比值是否与乳腺癌发病率的种族差异相关，以及（ii）编码P450芳香化酶蛋白的CYP 19基因的遗传变异是否与乳腺癌风险相关。在未行卵巢切除术的女性中，年龄和体重校正的种族特异性E1/A比值x 100在非裔美国人中为7.92，在日本人中为8.22，在拉丁美洲人中为10.73，在非拉丁美洲白人中为9.29（P=0.09）。拉丁裔女性的高E1/A比率与乳腺癌的高发病率无关;事实上，拉丁裔女性的乳腺癌发病率在迄今为止观察到的队列中最低。我们没有发现内含子（TTTA）（n）重复多态性与不同种族人群乳腺癌风险的一致关联。这种多态性与血浆E1/A比值的差异无关，无法预测其功能相关性。我们描述了一种新发现的与（TTTA）（n）重复多态性相关的CYP 19基因内含子5的TTC缺失，这种多态性和CYP 19基因外显子VII的密码子264的多态性都与乳腺癌无关。我们没有发现任何遗传变异的外显子VIII在54个非洲裔美国人的主题。我们确定了罕见的遗传变异未知的功能相关的启动子1.4的CYP 19基因在3的24个拉丁妇女。芳香化酶抑制剂作为乳腺癌化学预防药物的潜在用途取决于这些结果，因此进一步研究芳香化酶在乳腺癌病因学中的作用是重要的。
Based on experimental and epidemiological evidence it is hypothesized that estrogen increases breast cancer risk by increasing mitotic activity in breast epithelial cells. Aromatase is crucial to the biosynthesis of estrogens and may therefore play a role in breast cancer development. Supporting data for an etiological role of aromatase in breast tumor biology are several-fold. First, the association between weight and postmenopausal breast cancer risk may be mediated by aromatase. Secondly, a pilot study found a higher aromatase expression in normal breast adipose tissue from breast cancer cases as opposed to healthy women. Thirdly, experimental data in animals suggest that aromatase activity predisposes mammary tissue to preneoplastic and neoplastic changes. In a multiethnic cohort study conducted in Los Angeles and on Hawaii we investigated (i) whether the plasma estrone to androstenedione (E1/A) ratio in different ethnic groups was associated with ethnic differences in breast cancer incidence, and (ii) whether genetic variation in the CYP19 gene encoding the P450 aromatase protein was associated with breast cancer risk. The age- and weight-adjusted ethnic specific E1/A ratios x 100 among women without oophorectomy were 7.92 in African-Americans, 8.22 in Japanese, 10.73 in Latinas and 9.29 in non-latina Whites (P=0.09). The high E1/A ratio in Latina women was not associated with a high breast cancer incidence; in fact Latina women had the lowest breast cancer incidence in the cohort observed so far. We found no consistent association of an intronic (TTTA)(n) repeat polymorphism with breast cancer risk in different ethnic groups. This polymorphism was not associated with differences in the plasma E1/A ratio in a way that would predict its functional relevance. We describe a newly identified TTC deletion in intron 5 of the CYP19 gene that is associated with the (TTTA)(n) repeat polymorphism, Neither this polymorphism, nor a polymorphism at codon 264 in exon VII of the CYP19 gene, was associated with breast cancer. We did not identify any genetic variation in exon VIII in 54 African-American subjects. We identified rare genetic variants of unknown functional relevance in the promoter 1.4 of the CYP19 gene in 3 out of 24 Latina women. Further investigation into the role of aromatase in breast cancer etiology is important, given that the potential use of aromatase inhibitors as breast cancer chemopreventives depends on these results.