Influence of secreted frizzled receptor protein 1 (SFRP1) on neoadjuvant chemotherapy in triple negative breast cancer does not rely on WNT signaling.
Influence of secreted frizzled receptor protein 1 (SFRP1) on neoadjuvant chemotherapy in triple negative breast cancer does not rely on WNT signaling.
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DOI：
10.1186/1476-4598-13-174
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发表时间：
2014-07-17
期刊：
影响因子：
37.3
通讯作者：
Liedtke C
中科院分区：
文献类型：
--
作者：
Bernemann C;Hülsewig C;Ruckert C;Schäfer S;Blümel L;Hempel G;Götte M;Greve B;Barth PJ;Kiesel L;Liedtke C
三阴性乳腺癌（Triple negative breast cancer， TNBC）的特点是雌激素和孕激素受体均缺乏表达，HER2缺乏过表达或扩增。尽管对化疗反应的可能性增加，但与其他乳腺癌亚型相比，许多对当前化疗方案有耐药性的患者预后更差。然而，TNBC特异性化疗反应的分子决定因素在很大程度上仍然未知。因此，对于三阴性乳腺癌患者进行新辅助化疗或替代治疗的生物标志物有很高的需求。为了确定与三阴性乳腺癌亚型以及对新辅助化疗的反应相关的基因，我们使用了公开获得的接受新辅助化疗的患者的基因表达谱。组织微阵列分析以及乳腺癌细胞系揭示了与三阴性乳腺癌亚型的相关性。随后，分析了sirna介导的敲低对标准化疗药物和放射治疗反应的影响。此外，我们评估了SFRP1改变乳腺癌细胞致癌特性的分子机制。研究发现，与其他乳腺癌亚型相比，SFRP1在TNBC中显著过表达。此外，SFRP1的表达与新辅助化疗阳性反应的可能性增加显著相关。在三阴性乳腺癌细胞中敲低SFRP1使细胞对标准化疗更具抵抗力。此外，细胞的致瘤特性通过敲低而改变，如迁移或侵袭能力以及减少凋亡事件所示。令人惊讶的是，我们发现这些作用并不依赖于Wnt信号。此外，我们发现SFRP1敲低后，促凋亡和迁移途径受到不同的调节。我们首先可以证明SFRP1与三阴性乳腺癌亚型有很强的相关性，其次，SFRP1可以作为区分患者对新辅助化疗积极反应的标志物。肿瘤抑制因子SFRP1影响癌细胞致癌特性的机制并不依赖于Wnt信号，从而证明了肿瘤相关信号通路的复杂性。
Triple negative breast cancer (TNBC) is characterized by lack of expression of both estrogen and progesterone receptor as well as lack of overexpression or amplification of HER2. Despite an increased probability of response to chemotherapy, many patients resistant to current chemotherapy regimens suffer from a worse prognosis compared to other breast cancer subtypes. However, molecular determinants of response to chemotherapy specific to TNBC remain largely unknown. Thus, there is a high demand for biomarkers potentially stratifying triple negative breast cancer patients for neoadjuvant chemotherapies or alternative therapies. In order to identify genes correlating with both the triple negative breast cancer subtype as well as response to neoadjuvant chemotherapy we employed publicly available gene expression profiles of patients, which had received neoadjuvant chemotherapy. Analysis of tissue microarrays as well as breast cancer cell lines revealed correlation to the triple negative breast cancer subtype. Subsequently, effects of siRNA-mediated knockdown on response to standard chemotherapeutic agents as well as radiation therapy were analyzed. Additionally, we evaluated the molecular mechanisms by which SFRP1 alters the carcinogenic properties of breast cancer cells. SFRP1 was identified as being significantly overexpressed in TNBC compared to other breast cancer subtypes. Additionally, SFRP1 expression is significantly correlated with an increased probability of positive response to neoadjuvant chemotherapy. Knockdown of SFRP1 in triple negative breast cancer cells renders the cells more resistant to standard chemotherapy. Moreover, tumorigenic properties of the cells are modified by knockdown, as shown by both migration or invasion capacity as well reduced apoptotic events. Surprisingly, we found that these effects do not rely on Wnt signaling. Furthermore, we show that pro-apoptotic as well as migratory pathways are differentially regulated after SFRP1 knockdown. We could firstly show that SFRP1 strongly correlates with the triple negative breast cancer subtype and secondly, that SFRP1 might be used as a marker stratifying patients to positively respond to neoadjuvant chemotherapy. The mechanisms by which tumor suppressor SFRP1 influences carcinogenic properties of cancer cells do not rely on Wnt signaling, thereby demonstrating the complexity of tumor associated signaling pathways.
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