Kousidou O C, Mitropoulou T N, Roussidis A E, Kletsas D, Theocharis A D, Karamanos N K
Laboratory of Biochemistry, Section of Organic Chemistry, Biochemistry and Natural Products, Department of Chemistry, University of Patras, 261 10 Patras, Greece.
Int J Oncol. 2005 Apr;26(4):1101-9. doi: 10.3892/ijo.26.4.1101.
Progression of breast cancer implicates the degradation of extracellular matrix (ECM) by metallo-proteinases (MMPs), a process with important consequences on the growth and invasiveness of cancer cells in adjacent and distant sites. The isoflavone, genistein--a natural inhibitor of protein tyrosine kinase pathway--inhibits the growth of a wide range of cancer cells in vitro. The aim of this study was to investigate: i) the expression of mRNAs encoded for MMPs and their endogenous inhibitors (TIMPs) associated with pathogenesis and metastatic potential of breast cancer cells; and ii) the effect of genistein on the transcription of MMPs and TIMPs and the invasive potential of breast cancer cells. Gene expression at transcriptional level was examined in cell cultures of two epithelial breast cancer cell lines, the high invasive (ER-negative) MDA-MB-231 and the low invasive (ER-positive) MCF-7, as well as the normal mammary cells (MCF-12A) following RNA isolation and reversed transcriptase polymerase chain reaction (RT-PCR). The inhibitory effect of genistein on functional invasiveness was examined by a cell invasion assay. Cell cycle distribution showed that genistein arrested breast cancer MDA-MB-231, MCF-7 and BT-20 cells in the G2/M phase. Both normal and breast cancer cell lines express the genes of MMP-2, -9, MT1-, MT2-, MT3-MMP and TIMP-1, -2 and -3. MCF-7 express notably less MMPs than MDA-MB-231 cell line. The addition of genistein resulted in down-regulation of the transcription of all MMP genes in MDA-MB-231 and most of MMPs in MCF-7 cells. The inhibitory effect of genistein on MMPs was functionally confirmed, since it significantly reduced the invasion properties of cancer cells in vitro. The obtained results indicate that genistein may be of great value in prevention of breast cancer cell metastasis, since it represents both a transcriptional modulator of genes involved in this pathogenetic process and a suppressor of breast cancer cell invasiveness.
乳腺癌的进展涉及金属蛋白酶（MMPs）对细胞外基质（ECM）的降解，这一过程对癌细胞在邻近和远处部位的生长及侵袭性具有重要影响。异黄酮染料木黄酮是蛋白酪氨酸激酶途径的天然抑制剂，在体外可抑制多种癌细胞的生长。本研究旨在探讨：i）与乳腺癌细胞发病机制和转移潜能相关的MMPs及其内源性抑制剂（TIMPs）编码的mRNA表达；ii）染料木黄酮对MMPs和TIMPs转录以及乳腺癌细胞侵袭潜能的影响。在两种上皮性乳腺癌细胞系（高侵袭性（雌激素受体阴性）的MDA-MB-231和低侵袭性（雌激素受体阳性）的MCF-7）以及正常乳腺细胞（MCF-12A）的细胞培养物中，通过RNA分离和逆转录聚合酶链反应（RT-PCR）检测转录水平上的基因表达。通过细胞侵袭试验检测染料木黄酮对功能侵袭性的抑制作用。细胞周期分布显示，染料木黄酮使乳腺癌MDA-MB-231、MCF-7和BT-20细胞停滞于G2/M期。正常和乳腺癌细胞系均表达MMP-2、-9、MT1-、MT2-、MT3-MMP以及TIMP-1、-2和-3的基因。MCF-7表达的MMPs明显少于MDA-MB-231细胞系。添加染料木黄酮导致MDA-MB-231中所有MMP基因的转录下调，以及MCF-7细胞中大多数MMPs的转录下调。染料木黄酮对MMPs的抑制作用在功能上得到证实，因为它显著降低了癌细胞在体外的侵袭特性。所得结果表明，染料木黄酮在预防乳腺癌细胞转移方面可能具有重要价值，因为它既是参与这一发病过程的基因的转录调节因子，又是乳腺癌细胞侵袭性的抑制剂。
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