Chemokine receptor CXCR4-mediated transformation of mammary epithelial cells by enhancing multiple RTKs expression and deregulation of the p53/MDM2 axis.
Chemokine receptor CXCR4-mediated transformation of mammary epithelial cells by enhancing multiple RTKs expression and deregulation of the p53/MDM2 axis.
复制标题
趋化因子受体 CXCR4 通过增强多种 RTK 表达和解除 p53/MDM2 轴的调节来介导乳腺上皮细胞的转化。
DOI：
10.1016/j.canlet.2011.03.025
复制
发表时间：
2011
期刊：
影响因子：
9.7
通讯作者：
Tang,CareenK
中科院分区：
文献类型：
--
作者：
Su,Hua;SobrinoNajul,EliasJ;Toth,TheodoreA;Ng,CrystalMei;Lelievre,SophieA;Fred,Matthew;Tang,CareenK
最近的研究表明，CXCR 4与肿瘤转移有关。在高百分比的DCIS病例中也检测到CXCR 4水平升高。CXCR 4在DCIS中的高表达频率表明，许多DCIS病例具有侵袭性。在这项研究中，我们证明了CXCR 4的表达揭示了细胞的形态学改变，从正常的腺泡形态上皮细胞到3D培养系统中更具侵袭性的形态。CXCR 4异位表达诱导MCF-10A细胞侵袭有趣的是，CXCR 4能够协调信号网络中的复杂改变，包括多个受体酪氨酸激酶（RTK）的上调、p53/MDM 2轴的失调、E-cadherin和c-myc的上调以及细胞周期分子的调节以促进乳腺上皮细胞转化。这些发现表明，CXCR 4表达在乳腺病变的早期阶段发挥了关键作用，这可能解释了DCIS中检测到的CXCR 4表达的高频率。我们相信，这些研究将为乳腺癌的临床干预、预防和治疗带来新的、基于生物学的治疗策略。
Recent studies have shown that CXCR4 is associated with tumor metastasis. Elevated levels of CXCR4 are also detected in a high percentage of DCIS cases. The high frequency of CXCR4 expression in DCIS suggests that many DCIS cases are “primed” for invasiveness. In this study, we demonstrated that expression of CXCR4 reveals morphological alterations in cells, from normal acinar morphological epithelial cells to a more invasive morphology in a 3D-culture system. Ectopic expression of CXCR4 induces invasion of MCF-10A cells. Interestingly, CXCR4 is capable of orchestrating a complex alteration in signaling networks, which include upregulation of multiple receptor tyrosine kinases (RTKs), deregulation of p53/MDM2 axis, upregulation of E-cadherin and c-myc, as well as modulation of cell cycle molecules to facilitate mammary epithelia cell transformation. These findings reveal that CXCR4 expression exerts a critical role in early stages of breast lesions, which may explain the high frequency of CXCR4 expression detected in DCIS. We believe that these studies will lead to new, biologically-based therapeutic strategies for clinical intervention, prevention and treatments of breast cancer.