Estrogen receptors ERα and ERβ in proliferation in the rodent mammary gland
Estrogen receptors ERα and ERβ in proliferation in the rodent mammary gland
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DOI：
10.1073/pnas.0307864100
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发表时间：
2004-03-16
影响因子：
11.1
通讯作者：
Gustafsson, JA
中科院分区：
文献类型：
--
作者：
Cheng, GJ;Zhang, WH;Gustafsson, JA
大多数证据支持这样的观点，即ER α是负责雌激素（卵巢雌二醇，E-2）诱导的乳腺上皮细胞增殖，但尽管如此，增殖的上皮细胞不表达ER α。我们通过研究ER α和ER β在E-2诱导的乳腺增殖中的作用（通过BrdUrd掺入DNA来测量），研究了ER β基因完整的小鼠（WT小鼠）和ER β基因失活的小鼠（ER β（-/-）小鼠）中ER α和ER β在乳腺增殖中的作用。在用E-2处理ER β（-/-）小鼠或用E-2、他莫昔芬或特异性ER β激动剂（BAG）处理卵巢切除WT小鼠时，乳腺中BrdUrd标记细胞的数量从对照组的3.4%增加到处理小鼠的28-38%。这表明ER α和ER β都可以相互独立地介导E-2诱导的增殖。特异性抗体，ER β被发现在上皮和基质细胞，而ER α是严格的上皮。在4小时内的一个单一剂量的E-2，ER α从上皮细胞的细胞核丢失。在WT小鼠中，ER α在24小时后重新出现，但在ER β（-/-）小鼠中，返回细胞核延迟了24小时。在E-2后4小时，在BrdUrd标记的细胞核中检测不到ER α和孕酮受体，但在E-2后48小时，29%的BrdUrd标记的细胞表达ER α，21-38%的细胞表达孕酮受体。在连续3周的E-2治疗期间，ER β仍保留在细胞核中，但没有检测到ER α。用他莫昔芬治疗，ER α仍留在细胞核中，但ER β丢失。根据这些结果，我们得出结论，ER α从E-2接收增殖信号，启动DNA合成，然后从细胞中丢失。随后的增殖步骤可以在ER α或ER β不存在的情况下进行。ER β促进ER α返回细胞核并恢复对E-2的反应性。通过下调ER β，他莫昔芬可能延长乳腺上皮对E-2的不应性。
Most evidence supports the view that ERalpha is responsible for estrogen (ovarian estradiol, E-2)-induced proliferation in the epithelial cells of the mammary gland, but despite this, proliferating epithelial cells do not express ERalpha. We have examined this apparent paradox by studying the role of ERalpha and ERbeta in E-2-induced proliferation in mammary glands (measured by BrdUrd incorporation into DNA) in mice with intact ERbeta (WT mice) and those in which the ERbeta gene has been inactivated (ERbeta(-/-) mice). On treatment of ERbeta(-/-) mice with E-2 or ovariectomized WT mice with E-2, tamoxifen, or a specific ERbeta agonist (BAG), the number of BrdUrd-labeled cells in mammary glands increased from 3.4% in controls to 28-38% in the treated mice. This indicates that both ERalpha and ERbeta can mediate E-2-induced proliferation independently of each other. With specific antibodies, ERbeta was found in both epithelial and stromal cells, whereas ERalpha was strictly epithelial. Within 4 h of a single dose of E-2, ERalpha was lost from the nuclei of epithelial cells. In WT mice, ERalpha reappeared by 24 h, but in ERbeta(-/-) mice, return to the nucleus was delayed by 24 h. At 4 h after E-2, neither ERalpha nor progesterone receptor was detectable in BrdUrd-labeled nuclei but by 48 h after E-2, 29% of the BrdUrd-labeled cells expressed ERalpha, and 21-38% expressed progesterone receptor. During 3 weeks of continuous E-2 treatment, ERbeta remained in the nucleus, but there was no detectable ERalpha. With tamoxifen treatment, ERalpha remained in the nucleus, but ERbeta was lost. From these results, we conclude that ERalpha receives the proliferation signal from E-2, initiates DNA synthesis, and is then lost from cells. The subsequent steps in proliferation can proceed in the absence of either ERalpha or ERbeta. ERbeta facilitates the return of ERalpha to the nucleus and restores responsiveness to E-2. By down-regulating ERbeta, tamoxifen may prolong refractoriness to E-2 in mammary epithelium.