Aberrant activation of NF-κB signaling in mammary epithelium leads to abnormal growth and ductal carcinoma in situ.
Aberrant activation of NF-κB signaling in mammary epithelium leads to abnormal growth and ductal carcinoma in situ.
复制标题
DOI：
10.1186/s12885-015-1652-8
复制
发表时间：
2015-09-30
期刊：
影响因子：
3.8
通讯作者：
Yull FE
中科院分区：
文献类型：
--
作者：
Barham W;Chen L;Tikhomirov O;Onishko H;Gleaves L;Stricker TP;Blackwell TS;Yull FE
大约五分之一被诊断患有乳腺癌的女性被认为患有原位疾病，最常被称为导管原位癌（DCIS）。虽然被认为是发展更具侵袭性癌症的风险因素，但仍不清楚哪些因素有助于DCIS的发展。研究表明，炎症与多种肿瘤的发生发展有关，核因子κ B（NF-κB）是炎症信号传导的主要调节因子。然而，NF-κB信号转导对肿瘤发生的作用还不太清楚。全身性或乳腺局部的NF-κB活性异常上调可能是由于各种常见的刺激，如急性感染、肥胖或心理应激。在这项研究中，我们试图确定是否NF-κB在乳腺上皮细胞的激活可以发挥作用，在增生性导管病变的形成。我们的研究利用强力霉素诱导的转基因小鼠模型，其中组成型活性IKKβ在乳腺上皮特异性表达。所有先前发表的原始乳腺中NF-κB调节模型均为组成型模型，在动物的整个生命和发育过程中存在转基因或敲除。我们将首次在正常导管形成后的较晚时间点诱导激活，从而能够确定NF-κB激活是否能促进先前正常乳腺上皮的癌前病变。我们发现，即使是短脉冲的NF-κB激活也能诱导乳腺导管结构的深刻重塑。短期激活产生过度增殖、增大的导管和充满的管腔。炎症标志物表达的增加与激素受体和上皮分化标志物的下调同时发生。此外，已知在人类和小鼠DCIS中上调的癌蛋白粘蛋白1在活化的导管组织中过度表达和错误定位。这些结果表明，乳腺上皮内的异常NF-κB活化可导致与乳腺癌早期阶段一致的分子和形态学变化。因此，在急性炎症或增生性导管生长的初始体征后抑制NF-κB信号传导可能代表预防乳腺癌的重要机会。本文的在线版本（doi：10.1186/s12885-015-1652-8）包含补充材料，可供授权用户使用。
Approximately 1 in 5 women diagnosed with breast cancer are considered to have in situ disease, most often termed ductal carcinoma in situ (DCIS). Though recognized as a risk factor for the development of more invasive cancer, it remains unclear what factors contribute to DCIS development. It has been shown that inflammation contributes to the progression of a variety of tumor types, and nuclear factor kappa B (NF-κB) is recognized as a master-regulator of inflammatory signaling. However, the contributions of NF-κB signaling to tumor initiation are less well understood. Aberrant up-regulation of NF-κB activity, either systemically or locally within the breast, could occur due to a variety of commonly experienced stimuli such as acute infection, obesity, or psychological stress. In this study, we seek to determine if activation of NF-κB in mammary epithelium could play a role in the formation of hyperplastic ductal lesions. Our studies utilize a doxycycline-inducible transgenic mouse model in which constitutively active IKKβ is expressed specifically in mammary epithelium. All previously published models of NF-κB modulation in the virgin mammary gland have been constitutive models, with transgene or knock-out present throughout the life and development of the animal. For the first time, we will induce activation at later time points after normal ducts have formed, thus being able to determine if NF-κB activation can promote pre-malignant changes in previously normal mammary epithelium. We found that even a short pulse of NF-κB activation could induce profound remodeling of mammary ductal structures. Short-term activation created hyperproliferative, enlarged ducts with filled lumens. Increased expression of inflammatory markers was concurrent with the down-regulation of hormone receptors and markers of epithelial differentiation. Furthermore, the oncoprotein mucin 1, known to be up-regulated in human and mouse DCIS, was over-expressed and mislocalized in the activated ductal tissue. These results indicate that aberrant NF-κB activation within mammary epithelium can lead to molecular and morphological changes consistent with the earliest stages of breast cancer. Thus, inhibition of NF-κB signaling following acute inflammation or the initial signs of hyperplastic ductal growth could represent an important opportunity for breast cancer prevention. The online version of this article (doi:10.1186/s12885-015-1652-8) contains supplementary material, which is available to authorized users.