Estrogen promotes mammary tumor development in C3(1)/SV40 large T-antigen transgenic mice: paradoxical loss of estrogen receptoralpha expression during tumor progression.
Estrogen promotes mammary tumor development in C3(1)/SV40 large T-antigen transgenic mice: paradoxical loss of estrogen receptoralpha expression during tumor progression.
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发表时间：
2000-12
期刊：
影响因子：
11.2
通讯作者：
K. Yoshidome;Masa-Aki Shibata;Christine Couldrey;K. S. Korach;Jeffrey E. Green
中科院分区：
文献类型：
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作者：
K. Yoshidome;Masa-Aki Shibata;Christine Couldrey;K. S. Korach;Jeffrey E. Green
虽然一些流行病学证据表明，雌激素暴露影响乳腺癌的发病率的发展，雌激素可能刺激乳腺癌的形成的机制仍然知之甚少。我们已经探索了雌激素暴露的改变如何影响C3（1）/T（AG）转基因模型中乳腺癌的发展，其中雌激素水平和雌激素受体α（ER α）表达似乎不会改变转基因表达水平。C3（1）/T（AG）转基因在雌激素诱导的乳腺上皮原基分化为导管生长阶段后3周龄时在乳腺导管靶细胞中变得转录活跃。然而，乳腺导管树的完全成熟不是癌症发展所必需的，因为肿瘤发生在导管分支和末端芽形成被卵巢切除术过早阻止的动物中。在该模型中，雌激素暴露增加促进了乳腺肿瘤发生，并出现了显著更多的乳腺上皮内肿瘤病变和与加速恶性转化相关的癌。在该模型中，乳腺肿瘤的促进似乎是通过雌激素诱导的增殖和末端导管小叶单位转化可用靶细胞数量的增加而发生的，正如已经假定在接受激素替代疗法的女性中发生的那样和/或通过其他分子机制。我们首次在转基因小鼠模型中发现，乳腺肿瘤进展与ER α表达缺失相关，这在人类乳腺癌中经常观察到，具有重要的临床意义。因此，雌激素信号传导可能具有不同的功能，这取决于肿瘤发生的阶段。ER β表达在肿瘤进展过程中上调，尽管其功能意义仍有待确定。
Although several lines of epidemiological evidence suggest that estrogen exposure influences the incidence of breast cancer development, the mechanisms by which estrogen may stimulate the formation of breast cancer remain poorly understood. We have explored how alterations in estrogen exposure can influence the development of mammary cancer in the C3(1)/T(AG) transgenic model, where estrogen levels and estrogen receptor alpha (ERalpha) expression do not appear to modify the level of transgene expression. The C3(1)/T(AG) transgene becomes transcriptionally active in mammary ductal target cells at 3 weeks of age after the estrogen-induced differentiation of the mammary epithelial anlage to the ductal outgrowth stage. Complete maturation of the mammary ductal tree, however, is not required for cancer development because tumors arise in animals where ductal branching and terminal end bud formation have been prematurely arrested by ovariectomy. Mammary tumorigenesis in this model is promoted by increased estrogen exposure with the development of significantly more mammary intraepithelial neoplastic lesions and carcinomas associated with accelerated malignant conversion. The promotion of mammary tumors in this model appears to occur through an estrogen-induced proliferation and increase in the number of available target cells for transformation at the terminal ductal lobular units, as has been postulated to occur in women who receive hormone replacement therapy and/or by additional molecular mechanisms. We show, for the first time in a transgenic mouse model, that mammary tumor progression is associated with the loss of ERalpha expression, as has been often observed in human breast cancers with important clinical significance. Estrogen signaling may, therefore, serve different functions, depending upon the stage of tumorigenesis. ERbeta expression is up-regulated during tumor progression, although the functional significance of this remains to be determined.