Expression of the Pluripotency Transcription Factor OCT4 in the Normal and Aberrant Mammary Gland.
Expression of the Pluripotency Transcription Factor OCT4 in the Normal and Aberrant Mammary Gland.
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DOI：
10.3389/fonc.2013.00079
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发表时间：
2013
影响因子：
4.7
通讯作者：
Blancafort P
中科院分区：
文献类型：
--
作者：
Hassiotou F;Hepworth AR;Beltran AS;Mathews MM;Stuebe AM;Hartmann PE;Filgueira L;Blancafort P
具有泌乳特征的乳腺癌，其中一些与妊娠和哺乳相关，通常分化差，缺乏雌激素受体、孕激素受体和HER 2表达，死亡率高。对于这些肿瘤中驱动不受控制的细胞增殖并赋予泌乳功能的分子机制知之甚少。我们最近报道了OCT 4和相关胚胎干细胞自我更新基因在正常泌乳期乳腺和母乳干细胞（hBSC）中的表达。这促使我们使用罕见的人类哺乳期乳腺标本，研究具有哺乳期特征的乳腺癌中的OCT 4表达，并将其与正常哺乳期观察到的OCT 4表达进行比较。根据先前的文献，正常静息乳房（来自非妊娠、非哺乳期女性）显示最小的OCT 4核表达（0.9%）。然而，这在正常哺乳期乳腺中增加（11.4%），在哺乳期腺瘤、哺乳期癌和妊娠相关乳腺癌中进一步增加（30.7-48.3%）。OCT 4在上皮中表达，在基质中表达较低水平，并与NANOG共定位。正常非致瘤性hBSC与过表达OCT 4的致瘤性乳腺细胞系（OTBC）的比较表明，两种系统中OCT 4、SOX 2和NANOG均上调，但OTBC表达的OCT 4水平显著高于SOX 2和NANOG。与hBSC类似，OTBC显示出多谱系分化潜力，包括在体外和体内分化成合成乳蛋白的功能性乳细胞的能力。基于这些发现，我们提出了一个假设的正常和恶性转化的乳腺癌，其中集中在OCT 4及其相关的基因网络。虽然这些胚胎基因的最小表达可以看到在整个生命的休息状态下的乳房中，该基因网络的上调的控制程序可能是一个潜在的调节器的正常重塑的乳房在怀孕和哺乳期间的乳汁分泌器官。无论是在怀孕或哺乳期内或外，这种基因网络的失调可能会导致乳腺细胞异常增殖和恶性转化，这表明这些基因在正常哺乳和乳腺癌发生中的作用。
Breast cancers with lactating features, some of which are associated with pregnancy and lactation, are often poorly differentiated, lack estrogen receptor, progesterone receptor, and HER2 expression and have high mortality. Very little is known about the molecular mechanisms that drive uncontrolled cell proliferation in these tumors and confer lactating features. We have recently reported expression of OCT4 and associated embryonic stem cell self-renewal genes in the normal lactating breast and breastmilk stem cells (hBSCs). This prompted us to examine OCT4 expression in breast cancers with lactating features and compare it with that observed during normal lactation, using rare specimens of human lactating breast. In accordance with previous literature, the normal resting breast (from non-pregnant, non-lactating women) showed minimal OCT4 nuclear expression (0.9%). However, this increased in the normal lactating breast (11.4%), with further increase in lactating adenomas, lactating carcinomas, and pregnancy-associated breast cancer (30.7–48.3%). OCT4 was expressed in the epithelium and at lower levels in the stroma, and was co-localized with NANOG. Comparison of normal non-tumorigenic hBSCs with OCT4-overexpressing tumorigenic breast cell lines (OTBCs) demonstrated upregulation of OCT4, SOX2, and NANOG in both systems, but OTBCs expressed OCT4 at significantly higher levels than SOX2 and NANOG. Similar to hBSCs, OTBCs displayed multi-lineage differentiation potential, including the ability to differentiate into functional lactocytes synthesizing milk proteins both in vitro and in vivo. Based on these findings, we propose a hypothesis of normal and malignant transformation in the breast, which centers on OCT4 and its associated gene network. Although minimal expression of these embryonic genes can be seen in the breast in its resting state throughout life, a controlled program of upregulation of this gene network may be a potential regulator of the normal remodeling of the breast toward a milk-secretory organ during pregnancy and lactation. Deregulation of this gene network either within or outside pregnancy and lactation may lead to aberrant breast cell proliferation and malignant transformation, suggesting a role of these genes in both normal lactation and breast oncogenesis.