INSERM U 908 Growth factor signaling in breast cancer cells. Functional proteomics, IFR-147, University of Lille, Villeneuve d'Ascq, France.
Clin Cancer Res. 2011 Apr 1;17(7):1741-52. doi: 10.1158/1078-0432.CCR-10-1890. Epub 2011 Feb 24.
Given that nerve growth factor has previously been shown to be involved in breast cancer progression, we have tested here the hypothesis that the other neurotrophins (NT) are expressed and have an influence in breast tumor growth.
The expression of brain-derived neurotrophic factor (BDNF), NT-3 and NT-4/5, as well as the neurotrophin receptor p75(NTR), TrkB, and TrkC, was studied by RT-PCR, Western blotting, and immunohistochemistry in cell lines and tumor biopsies. The biological impacts of neurotrophins, and associated mechanisms, were analyzed in cell cultures and xenografted mice.
BDNF and NT-4/5 were expressed and secreted by breast cancer cells, and the use of blocking antibodies suggested an autocrine loop mediating cell resistance to apoptosis. The corresponding tyrosine kinase receptor TrkB was only rarely observed at full length, whereas the expression of TrkB-T1, lacking the kinase domain, as well as p75(NTR), were detected in all tested breast cancer cell lines and tumor biopsies. In contrast, NT-3 and TrkC were not detected. SiRNA against p75(NTR) and TrkB-T1 abolished the antiapoptotic effect of BDNF and NT-4/5, whereas the pharmacological inhibitors K252a and PD98059 had no effect, suggesting the involvement of p75(NTR) and TrkB-T1, but not kinase activities from Trks and MAPK. In xenografted mice, anti-BDNF, anti-NT-4/5, anti-p75(NTR), or anti-TrkB-T1 treatments resulted in tumor growth inhibition, characterized by an increase in cell apoptosis, but with no change in proliferation.
BDNF and NT-4/5 contribute to breast cancer cell survival and can serve as prospective targets in attempts to inhibit tumor growth.
鉴于神经生长因子先前已被证明参与乳腺癌的进展，我们在这里测试了以下假设，即其他神经营养因子（NT）在乳腺肿瘤生长中表达并具有影响。
通过 RT-PCR、Western blot 和免疫组织化学方法研究了脑源性神经营养因子（BDNF）、NT-3 和 NT-4/5 以及神经营养因子受体 p75（NTR）、TrkB 和 TrkC 在细胞系和肿瘤活检中的表达。在细胞培养物和异种移植小鼠中分析了神经营养因子的生物学影响及其相关机制。
BDNF 和 NT-4/5 由乳腺癌细胞表达和分泌，使用阻断抗体表明介导细胞抵抗细胞凋亡的自分泌环。全长 TrkB 很少观察到相应的酪氨酸激酶受体，而检测到所有测试的乳腺癌细胞系和肿瘤活检中 TrkB-T1（缺乏激酶结构域）和 p75（NTR）的表达。相反，未检测到 NT-3 和 TrkC。针对 p75（NTR）和 TrkB-T1 的 siRNA 消除了 BDNF 和 NT-4/5 的抗凋亡作用，而药理学抑制剂 K252a 和 PD98059 没有作用，表明 p75（NTR）和 TrkB-T1 的参与，但不是 Trks 和 MAPK 的激酶活性。在异种移植小鼠中，抗 BDNF、抗 NT-4/5、抗 p75（NTR）或抗 TrkB-T1 治疗导致肿瘤生长抑制，其特征为细胞凋亡增加，但增殖无变化。
BDNF 和 NT-4/5 有助于乳腺癌细胞的存活，可以作为抑制肿瘤生长的潜在靶点。
