Ford Caroline E, Ekström Elin J, Howlin Jillian, Andersson Tommy
Cell and Experimental Pathology, Department of Laboratory Medicine, Lund University, Malmö University Hospital, Malmö, Sweden.
Cell Cycle. 2009 Jun 15;8(12):1838-42. doi: 10.4161/cc.8863. Epub 2009 Jun 27.
Despite improvements in detection and treatment, breast cancer remains the most common female cancer worldwide, and metastatic associated mortality is a significant public health issue. Patients with tumors negative for estrogen receptor (ERalpha), have a particularly poor prognosis, partly due to their inability to respond to current endocrine treaments. Expression of Wnt-5a has been associated with prolonged recurrence free survivial in clinical material, and Wnt-5a also inhibits migration and invasion of breast cancer cell lines. Loss of Wnt-5a is associated with loss of ERalpha in clinical breast cancer material, and Wnt-5a signaling upregulates ERalpha in ERalpha negative breast cancer cell lines. A Wnt-5a derived hexapeptide, Foxy-5, has been developed and like Wnt-5a, increases adhesion and inhibits migration of breast cancer cells. Furthermore, Foxy-5 significantly reduced liver and lung metastases in a murine ERalpha negative breast cancer model. Foxy-5 also upregulated ERalpha in this in vivo model and most significantly, in vitro rendered cells responsive to the selective estrogen receptor modulator, Tamoxifen. Together these studies suggest that Foxy-5 may be a potential new supplementary treatment for ERalpha negative breast cancer patients, as it addresses two of the most important aspects of cancer related mortality -- non response to endocrine therapy and metastasis.
尽管在检测和治疗方面有所改进，但乳腺癌仍然是全球最常见的女性癌症，且转移相关死亡率是一个重大的公共卫生问题。雌激素受体（ERα）阴性的肿瘤患者预后特别差，部分原因是他们无法对当前的内分泌治疗产生反应。Wnt-5a的表达与临床样本中无复发生存期的延长相关，并且Wnt-5a还抑制乳腺癌细胞系的迁移和侵袭。在临床乳腺癌样本中，Wnt-5a的缺失与ERα的缺失相关，并且Wnt-5a信号通路在ERα阴性乳腺癌细胞系中上调ERα。一种源自Wnt-5a的六肽Foxy-5已被研发出来，与Wnt-5a一样，它能增加乳腺癌细胞的黏附并抑制其迁移。此外，在小鼠ERα阴性乳腺癌模型中，Foxy-5显著减少了肝脏和肺部转移。在这个体内模型中，Foxy-5还上调了ERα，最显著的是，在体外使细胞对选择性雌激素受体调节剂他莫昔芬产生反应。这些研究共同表明，Foxy-5可能是ERα阴性乳腺癌患者潜在的新辅助治疗方法，因为它解决了癌症相关死亡率的两个最重要方面——对内分泌治疗无反应和转移。
