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首页> 外文期刊>Oncogene >Aromatase overexpression induces malignant changes in estrogen receptor α negative MCF-10A cells
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Aromatase overexpression induces malignant changes in estrogen receptor α negative MCF-10A cells

机译：芳香酶过度表达诱导雌激素受体α阴性MCF-10A细胞恶变

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Estrogen is a risk factor of breast cancer. Elevated expression of aromatase (estrogen synthase) in breast tissues increases local estradiol concentrations and is associated with breast cancer development, but the causal relationship between aromatase and breast cancer has not been identified. Accumulating data suggest that both estrogen receptor (ER)-dependent and -independent effects are involved in estrogen carcinogenesis. We established a model by expressing aromatase in ER伪鈭?MCF-10A human breast epithelial cells to investigate ER伪-independent effects of estrogen in the process of malignant transformation. Overexpression of aromatase significantly increased anchorage-independent growth. Parental- or vector-expressing MCF-10A cells did not form colonies under the same conditions. The anchorage-independent growth of MCF-10A~(arom) cells can be completely abolished by pre-treatment with the aromatase inhibitor, letrozole. Neither MCF-10A~(arom) nor MCF-10A~(vector) cells grown in monolayer were affected by short-term exposure to estradiol. Enhanced motility is another characteristic of cellular transformation. Motility of MCF-10A~(arom) cells was increased, which could be inhibited by letrozole. Increases in stem cell population in breast cancer tissues are associated with tumor recurrence and metastasis. CD44~(high)/CD24~(low) is a stem cell marker. We found that CD24 mRNA levels were reduced in MCF-10A~(arom) cells compared with those in parental- and vector-transfected cells. By examining individual clones of MCF-10A~(arom) with various aromatase activities, we found that the CD24 mRNA levels were inversely correlated with aromatase activity. The ability of MCF-10A~(arom) cells to form mammospheres in the absence of serum was increased. Our results suggest that overexpression of aromatase in MCF-10A cells causes malignant transformation. Estrogen metabolite-mediated genotoxicity and induction of a stem cell/progenitor cell population are possible mechanisms. These studies provide additional evidence for ER伪-independent mechanism(s) in estrogen carcinogenesis and implicate superiority of aromatase inhibitors to antiestrogens for breast cancer prevention.
机译：雌激素是乳腺癌的危险因素。乳腺组织中芳香化酶（雌激素合酶）的表达升高会增加局部雌二醇的浓度，并与乳腺癌的发展有关，但芳香化酶与乳腺癌之间的因果关系尚未确定。越来越多的数据表明，雌激素受体（ER）依赖性和非依赖性作用均与雌激素致癌作用有关。我们通过在ERα鈭MCF-10A人乳腺上皮细胞中表达芳香酶建立了模型，以研究雌激素在恶性转化过程中不依赖ERα的作用。芳香化酶的过表达显着增加了锚定非依赖性生长。在相同条件下，表达亲本或载体的MCF-10A细胞不形成菌落。通过用芳香化酶抑制剂来曲唑进行预处理，可以完全消除MCF-10A〜（arom）细胞的不依赖贴壁的生长。单层生长的MCF-10A〜（arom）细胞或MCF-10A〜（vector）细胞均不受短期暴露于雌二醇的影响。运动能力增强是细胞转化的另一个特征。 MCF-10A〜（arom）细胞的运动性增加，这可能被来曲唑抑制。乳腺癌组织中干细胞数量的增加与肿瘤的复发和转移有关。 CD44〜（高）/ CD24〜（低）是干细胞标记。我们发现与亲本和载体转染的细胞相比，MCF-10A〜（arom）细胞中的CD24 mRNA水平降低。通过检查具有各种芳香化酶活性的单个MCF-10A〜（arom）克隆，我们发现CD24 mRNA水平与芳香化酶活性呈负相关。在没有血清的情况下，MCF-10A〜（arom）细胞形成乳球的能力增加。我们的结果表明，MCF-10A细胞中芳香酶的过度表达会导致恶性转化。雌激素代谢物介导的遗传毒性和干细胞/祖细胞群的诱导是可能的机制。这些研究为雌激素致癌作用中不依赖ERα的机制提供了额外的证据，并暗示了芳香酶抑制剂在抗雌激素预防乳腺癌方面的优越性。

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