Loss of primary cilia occurs early in breast cancer development.
Loss of primary cilia occurs early in breast cancer development.
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作者：
Menzl I;Lebeau L;Pandey R;Hassounah NB;Li FW;Nagle R;Weihs K;McDermott KM
初级纤毛是从细胞表面伸出的微管细胞器。初级纤毛通过调控包括刺猬信号通路在内的信号通路在发育和疾病中发挥关键作用。最近的小鼠模型也将纤毛功能障碍与癌症联系起来。然而，人们对原发性纤毛在乳腺癌发展中的作用知之甚少。通过计数纤毛和测量纤毛长度，研究了86例乳腺癌患者的癌细胞及其周围基质细胞中纤毛的表达特征。此外，我们检查了纤毛在缩小乳房成形术的正常上皮细胞和基质细胞以及组织学上正常的邻近组织中的表达进行比较。我们观察到纤毛细胞在癌前病变和浸润性癌症中的百分比有统计学意义的下降。纤毛的缺失与增殖指数（ki67阳性细胞）的增加无关。然而，我们确实在浸润性乳腺癌患者中发现了罕见的纤毛癌细胞，并发现这些细胞表达与预后不良相关的基底细胞癌标志物（细胞角蛋白5）。有趣的是，与正常组织相关的间质细胞相比，与癌前病变和浸润性癌症相关的纤毛间质细胞的百分比都有所下降。为了了解纤毛在癌症发展过程中是如何丢失的，我们分析了纤毛发生和/或纤毛功能所需基因的表达，并比较了它们在正常和乳腺癌样本中的表达。我们发现纤毛基因的表达在人类乳腺癌中经常下调。这些数据表明，原发性纤毛在乳腺癌细胞及其周围基质细胞的早期发展中都丢失了。
Primary cilia are microtubule-based organelles that protrude from the cell surface. Primary cilia play a critical role in development and disease through regulation of signaling pathways including the Hedgehog pathway. Recent mouse models have also linked ciliary dysfunction to cancer. However, little is known about the role of primary cilia in breast cancer development. Primary cilia expression was characterized in cancer cells as well as their surrounding stromal cells from 86 breast cancer patients by counting cilia and measuring cilia length. In addition, we examined cilia expression in normal epithelial and stromal cells from reduction mammoplasties as well as histologically normal adjacent tissue for comparison. We observed a statistically significant decrease in the percentage of ciliated cells on both premalignant lesions as well as in invasive cancers. This loss of cilia does not correlate with increased proliferative index (Ki67-positive cells). However, we did detect rare ciliated cancer cells present in patients with invasive breast cancer and found that these express a marker of basaloid cancers that is associated with poor prognosis (Cytokeratin 5). Interestingly, the percentage of ciliated stromal cells associated with both premalignant and invasive cancers decreased when compared to stromal cells associated with normal tissue. To understand how cilia may be lost during cancer development we analyzed the expression of genes required for ciliogenesis and/or ciliary function and compared their expression in normal versus breast cancer samples. We found that expression of ciliary genes were frequently downregulated in human breast cancers. These data suggest that primary cilia are lost early in breast cancer development on both the cancer cells and their surrounding stromal cells.