BDNF is associated with SFRP1 expression in luminal and basal-like breast cancer cell lines and primary breast cancer tissues: a novel role in tumor suppression?
BDNF is associated with SFRP1 expression in luminal and basal-like breast cancer cell lines and primary breast cancer tissues: a novel role in tumor suppression?
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DOI：
10.1371/journal.pone.0102558
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Dahl E
中科院分区：
文献类型：
--
作者：
Huth L;Rose M;Kloubert V;Winkens W;Schlensog M;Hartmann A;Knüchel R;Dahl E
分泌型卷曲相关蛋白1（SFRP 1）作为Wnt途径的重要抑制剂发挥作用，并且是已知的肿瘤抑制基因，其在多种肿瘤（例如乳腺癌）中表观遗传学沉默。然而，目前还不清楚SFRP 1究竟如何影响Wnt通路。我们的目的是破译SFRP 1参与生化信号依赖于不同的乳腺癌亚型，并确定新的SFRP 1调节基因。我们通过使用基底样BT20和管腔样HER2阳性SKBR 3细胞产生SFRP 1过表达的体外乳腺癌模型，反映了两种主要亚型。这些模型的DNA微阵列表达谱显示，除了对Wnt信号传导的已知影响外，SFRP 1表达还可能调节骨形态发生蛋白和Smoothened信号传导（p<0.01）。重要的是，进一步的统计分析显示，依赖于癌症亚型模型，SFRP 1可能分别影响经典和非经典Wnt途径（p<0.01）。虽然SFRP 1再表达通常介导BT20和SKBR 3细胞中转录诱导或抑制基因的不同模式，但脑源性神经营养因子（BDNF）在两种细胞系中均被鉴定为SFRP 1诱导的基因。尽管BDNF被认为是一种假定的癌基因，但与SFRP 1的共调节表明其在乳腺癌中具有潜在的抑制功能。事实上，在原发性乳腺癌样品中，SFRP 1和BDNF蛋白表达之间可以显示出正相关性（p<0.001）。此外，基于TCGA数据集的分析清楚地强调，BDNF mRNA在原发性乳腺癌样本中下调，预测这些患者的预后不良。与此同时，我们在功能上提供了在基底样BT20乳腺癌细胞中稳定的BDNF再表达阻断肿瘤细胞增殖的证据。因此，我们的研究结果表明，BDNF可能会在人类乳腺癌中介导抑制功能，而不是促进功能，其作用模式应在未来的研究中得到解决。
Secreted frizzled related protein 1 (SFRP1) functions as an important inhibitor of the Wnt pathway and is a known tumor suppressor gene, which is epigenetically silenced in a variety of tumors e.g. in breast cancer. However, it is still unclear how SFRP1 exactly affects the Wnt pathway. Our aim was to decipher SFRP1 involvement in biochemical signaling in dependency of different breast cancer subtypes and to identify novel SFRP1-regulated genes. We generated SFRP1 over-expressing in vitro breast cancer models, reflecting the two major subtypes by using basal-like BT20 and luminal-like HER2-positive SKBR3 cells. DNA microarray expression profiling of these models revealed that SFRP1 expression potentially modulates Bone morphogenetic protein- and Smoothened signaling (p<0.01), in addition to the known impact on Wnt signaling. Importantly, further statistical analysis revealed that in dependency of the cancer subtype model SFRP1 may affect the canonical and non-canonical Wnt pathway (p<0.01), respectively. While SFRP1 re-expression generally mediated distinct patterns of transcriptionally induced or repressed genes in BT20 and SKBR3 cells, brain derived neurotrophic factor (BDNF) was identified as a SFRP1 induced gene in both cell lines. Although BDNF has been postulated as a putative oncogene, the co-regulation with SFRP1 indicates a potential suppressive function in breast cancer. Indeed, a positive correlation between SFRP1 and BDNF protein expression could be shown (p<0.001) in primary breast cancer samples. Moreover, TCGA dataset based analysis clearly underscores that BDNF mRNA is down-regulated in primary breast cancer samples predicting a poor prognosis of these patients. In line, we functionally provide evidence that stable BDNF re-expression in basal-like BT20 breast cancer cells blocks tumor cell proliferation. Hence, our results suggest that BDNF might rather mediate suppressive than promoting function in human breast cancer whose mode of action should be addressed in future studies.
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DOI：
10.1186/bcr3236
发表时间：
2012-07-27
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Fredlund E;Staaf J;Rantala JK;Kallioniemi O;Borg A;Ringnér M
通讯作者：
Ringnér M
影响因子：
4.8
作者：
Hussein, SM;Duff, EK;Sirard, C
通讯作者：
Sirard, C
影响因子：
11.2
作者：
Caldwell, GM;Jones, C;Morton, DG
通讯作者：
Morton, DG
影响因子：
4
作者：
Huelsken, J;Behrens, J
通讯作者：
Behrens, J
影响因子：
1.8
作者：
Chen, D;Zhao, M;Mundy, GR
通讯作者：
Mundy, GR