Profilin-1 is a negative regulator of mammary carcinoma aggressiveness.
Profilin-1 is a negative regulator of mammary carcinoma aggressiveness.
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DOI：
10.1038/sj.bjc.6604038
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发表时间：
2007-11-19
影响因子：
8.8
通讯作者：
Roy, P.
中科院分区：
文献类型：
--
作者：
Zou, L.;Jaramillo, M.;Whaley, D.;Wells, A.;Panchapakesa, V.;Das, T.;Roy, P.
profilin-1（Pfn 1）的表达在乳腺癌细胞中下调，其功能意义尚待了解。为了解决这个问题，在这项研究中，我们评估了干扰Pfn 1如何影响乳腺癌细胞的运动和侵袭。我们发现Pfn 1表达的缺失导致MDA-MB-231乳腺癌细胞的运动性和基质胶侵袭性增强。有趣的是，沉默Pfn 1的表达与下调细胞-细胞和细胞-基质粘附伴随着运动性的增加和显着的散射正常人乳腺上皮细胞。因此，这些数据首次表明Pfn 1表达的缺失可能在乳腺癌进展中具有重要意义。与这些发现相一致，即使Pfn 1的适度过表达也会诱导肌动蛋白应力纤维，上调粘着斑，并显著抑制MDA-MB-231细胞的运动性和基质胶侵袭性。使用突变体的Pfn 1是有缺陷的结合肌动蛋白或脯氨酸丰富的配体，我们进一步表明，过表达的Pfn 1必须有一个功能性肌动蛋白结合位点，以抑制细胞运动。最后，动物实验显示Pfn 1的过表达抑制了裸鼠中MDA-MB-231细胞的原位成瘤性和微转移。这些数据意味着干扰Pfn 1可能是限制乳腺癌细胞侵袭性的良好分子策略。
Expression of profilin-1 (Pfn1) is downregulated in breast cancer cells, the functional significance of which is yet to be understood. To address this question, in this study we evaluated how perturbing Pfn1 affects motility and invasion of breast cancer cells. We show that loss of Pfn1 expression leads to enhanced motility and matrigel invasiveness of MDA-MB-231 breast cancer cells. Interestingly, silencing Pfn1 expression is associated with downregulation of both cell–cell and cell–matrix adhesions with concomitant increase in motility and dramatic scattering of normal human mammary epithelial cells. Thus, these data for the first time suggest that loss of Pfn1 expression may have significance in breast cancer progression. Consistent with these findings, even a moderate overexpression of Pfn1 induces actin stress-fibres, upregulates focal adhesion, and dramatically inhibits motility and matrigel invasiveness of MDA-MB-231 cells. Using mutants of Pfn1 that are defective in binding to either actin or proline-rich ligands, we further show that overexpressed Pfn1 must have a functional actin-binding site to suppress cell motility. Finally, animal experiments reveal that overexpression of Pfn1 suppresses orthotopic tumorigenicity and micro-metastasis of MDA-MB-231 cells in nude mice. These data imply that perturbing Pfn1 could be a good molecular strategy to limit the aggressiveness of breast cancer cells.
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