FRA-1 expression level regulates proliferation and invasiveness of breast cancer cells
FRA-1 expression level regulates proliferation and invasiveness of breast cancer cells
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DOI：
10.1038/sj.onc.1208312
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发表时间：
2005-02-17
期刊：
影响因子：
8
通讯作者：
Chalbos, D
中科院分区：
文献类型：
--
作者：
Belguise, K;Kersual, N;Chalbos, D
乳腺癌的进展可能是一个涉及许多基因激活和失活的多步骤过程。先前，我们发现编码Fra - 1（一种FOS家族成员和AP - 1转录因子成分）的mRNA在侵袭性更强的雌激素受体阴性（ER -）乳腺癌细胞系中高度表达。我们使用四环素调控系统在MCF7 ER +细胞中稳定过表达Fra - 1，并评估Fra - 1对这种侵袭性表型的影响。相反，我们使用RNA干扰技术在高侵袭性的ER - MDA - MB231细胞中沉默Fra - 1。我们报道在这两种系统中，Fra - 1的表达水平与体外评估的细胞增殖、细胞运动性和侵袭性呈正相关。此外，在成纤维细胞样ER -细胞中抑制Fra - 1（这些细胞在基质胶中形成带有大的星状突起的集落）会导致形态变化。细胞在基质胶中呈现上皮样形状且呈球形。Fra - 1调节了几个与侵袭、血管生成和细胞增殖有关的基因，且这种调节不依赖于β1 -整合素的激活，并且Fra - 1直接诱导MMP - 1和MMP - 9启动子的活性。这些总体结果表明，Fra - 1的高表达与更恶性的细胞表型相关，并提示Fra - 1可能在乳腺癌进展中起关键作用。
Breast cancer progression is likely a multistep process involving the activation and inactivation of a number of genes. Previously, we showed that the mRNA coding for Fra-1, a FOS family member and an AP-1 transcription factor component, was highly expressed in the more invasive estrogen receptor negative (ER-) breast cancer cell lines. We used a tet-off system to stably overexpress Fra-1 in MCF7 ER + cells and evaluate the impact of Fra-1 on this aggressive phenotype. Conversely, Fra-1 was silenced in highly invasive ER-MDA-MB231 cells using RNA interference. We report that in both systems the Fra-1 expression level was positively associated with cell proliferation, cell motility and invasiveness assessed in vitro. In addition, Fra-1 inhibition in fibroblastoid ER-cells, which formed colonies with large stellate projections in Matrigel, resulted in morphological changes. Cells acquired an epithelioid shape and had a spherical appearance in Matrigel. Fra-1 regulated several genes, implicated in invasion, angiogenesis and cell proliferation independently of beta1-integrin activation, and directly induced MMP-1 and MMP-9 promoter activity. These overall results show that high Fra-1 expression is associated with a more malignant cell phenotype and suggest that Fra-1 could have a pivotal role in breast cancer progression.