Estrogen regulates luminal progenitor cell differentiation through H19 gene expression.
Estrogen regulates luminal progenitor cell differentiation through H19 gene expression.
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DOI：
10.1530/erc-15-0105
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发表时间：
2015-08
影响因子：
3.9
通讯作者：
Raouf A
中科院分区：
文献类型：
--
作者：
Basak P;Chatterjee S;Weger S;Bruce MC;Murphy LC;Raouf A
虽然雌激素信号传导在乳腺癌发展中的作用已被广泛研究，但调节雌激素在正常乳腺发育中不可或缺的作用的机制尚未得到充分研究。由于体外培养系统不能维持雌激素受体阳性（ERα+）细胞，因此调节正常人乳腺雌激素/ERα信号转导的分子机制尚不清楚。在本研究中，我们使用改良的基质胶测定法检测了雌激素信号对ERα+人管腔祖细胞的影响，发现雌激素信号增加了这些祖细胞的扩增潜力。此外，我们发现阻断ERα减弱了管腔祖细胞的扩增，并降低了这些祖细胞的管腔集落形成潜力。此外，阻断ERα降低了管腔祖细胞中的H19表达，并导致较小管腔集落的发育。我们进一步表明，敲除管腔祖细胞中的H19基因显著降低了管腔祖细胞的集落形成潜力，并且这种表型不能通过添加雌激素来挽救。最后，我们探索了雌激素-H19信号轴在乳腺肿瘤中的临床相关性，发现ERα+肿瘤比ERα−肿瘤表现出更高的H19表达，并且在这些肿瘤中H19表达与ERα表达呈正相关。综上所述，本研究结果表明，雌激素-ER α-H19信号轴在调节正常管腔祖细胞的增殖和分化潜能中起作用，并且该信号网络在ER+乳腺癌肿瘤的发展中也可能是重要的。
Although the role of estrogen signaling in breast cancer development has been extensively studied, the mechanisms that regulate the indispensable role of estrogen in normal mammary gland development have not been well studied. Because of the unavailability of culture system to maintain estrogen-receptor-positive (ERα+) cells in vitro, the molecular mechanisms that regulate estrogen/ERα signaling in the normal human breast are unknown. In the present study, we examined the effects of estrogen signaling on ERα+ human luminal progenitors using a modified matrigel assay and found that estrogen signaling increased the expansion potential of these progenitors. Furthermore, we found that blocking ERα attenuated luminal progenitor expansion and decreased the luminal colony-forming potential of these progenitors. Additionally, blocking ERα decreased H19 expression in the luminal progenitors and led to the development of smaller luminal colonies. We further showed that knocking down the H19 gene in the luminal progenitors significantly decreased the colony-forming potential of the luminal progenitors, and this phenotype could not be rescued by the addition of estrogen. Lastly, we explored the clinical relevance of the estrogen–H19 signaling axis in breast tumors and found that ERα+ tumors exhibited a higher expression of H19 as compared with ERα− tumors and that H19 expression showed a positive correlation with ERα expression in those tumors. Taken together, the present results indicate that the estrogen–ERα–H19 signaling axis plays a role in regulating the proliferation and differentiation potentials of the normal luminal progenitors and that this signaling network may also be important in the development of ER+ breast cancer tumors.