CCN5/WISP-2 expression in breast adenocarcinoma is associated with less frequent progression of the disease and suppresses the invasive phenotypes of tumor cells
CCN5/WISP-2 expression in breast adenocarcinoma is associated with less frequent progression of the disease and suppresses the invasive phenotypes of tumor cells
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DOI：
10.1158/0008-5472.can-08-1461
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发表时间：
2008-09-15
期刊：
影响因子：
11.2
通讯作者：
Banerjee, Sushanta K.
中科院分区：
文献类型：
--
作者：
Banerjee, Snigdha;Dhar, Gopal;Banerjee, Sushanta K.
尽管先前的体外研究预测CCN 5/WISP-2可能在乳腺癌中起抗侵袭基因的作用，但CCN 5在乳腺癌样品中的分布模式是矛盾的。因此，我们系统地研究了CCN 5在非侵袭性和侵袭性乳腺肿瘤样本中的表达谱及其在乳腺癌进展中的功能相关性。研究表明，CCN 5的表达是双相的，因此在正常样本中CCN 5的表达是检测不到的，而其表达在非侵袭性乳腺病变中显著增加，包括非典型导管增生和导管原位癌。此外，CCN 5 mRNA和蛋白质水平随着癌症从非侵入性发展到侵入性类型而显著降低。此外，我们发现，与中分化或高分化样本相比，低分化癌症中CCN 5 mRNA和蛋白水平几乎检测不到，其表达与淋巴结阳性呈负相关。通过使用实时PCR分析评价显微切片中的RNA表达谱进一步支持该结果。因此，我们的数据表明CCN 5在非侵袭性乳腺肿瘤细胞中具有保护功能。我们的体外研究进一步支持了这一假设，表明CCN 5是乳腺癌细胞迁移和侵袭的负调节因子，并且这些事件可以通过CCN 5调节侵袭前沿所必需的基因的表达。这些包括Snail-E-钙粘蛋白信号传导和基质金属蛋白酶（MMP）-9和MMP-2。总的来说，这些研究表明CCN 5在乳腺癌进展中的保护作用可能具有重要的治疗意义。
Although previous in vitro studies predicted that CCN5/WISP-2 may act as an anti-invasive gene in breast cancer, the distribution pattern of CCN5 in breast cancer samples is conflicting. Thus, we systematically investigated the CCN5 expression profile in noninvasive and invasive breast tumor samples and its functional relevance in breast cancer progression. The studies showed that CCN5 expression is biphasic, such that in normal samples CCN5 expression is undetectable, whereas its expression is markedly increased in noninvasive breast lesions, including atypical ductal hyperplasia and ductal carcinoma in situ. Further, CCN5 mRNA and protein levels are significantly reduced as the cancer progresses from a noninvasive to invasive type. Additionally, we showed that CCN5 mRNA and protein level was almost undetectable in poorly differentiated cancers compared with the moderately or well-differentiated samples and its expression inversely correlated with lymph node positivity. The result was further supported by evaluating the RNA expression profile in microdissected sections using real-time PCR analysis. Therefore, our data suggest a protective function of CCN5 in noninvasive breast tumor cells. This hypothesis was further supported by our in vitro studies illuminating that CCN5 is a negative regulator of migration and invasion of breast cancer cells, and these events could be regulated by CCN5 through the modulation of the expression of genes essential for an invasive front. These include Snail-E-cadherin signaling and matrix metalloproteinase (MMP)-9 and MMP-2. Collectively, these studies suggest that the protective effect of CCN5 in breast cancer progression may have important therapeutic implications.