Joshi Sonali, Yang Jun, Wang Qingfei, Li Ping, Wang Hai, Zhang Qingling, Xiong Yan, Pickering Brian F, Parker-Thornburg Jan, Behringer Richard R, Yu Dihua
Department of Molecular & Cellular Oncology, The University of Texas MD Anderson Cancer CenterHouston, Texas 77030, USA.
University of Texas Health Science Center Graduate School of Biomedical SciencesHouston, Texas 77030, USA.
Am J Cancer Res. 2017 Aug 1;7(8):1654-1664. eCollection 2017.
The 14-3-3ζ protein belongs to the 14-3-3 family of regulatory eukaryotic proteins that modulate signaling by binding to wide variety of signaling molecules. 14-3-3ζ expression is amplified in over 40% breast cancer patients and is associated with a poor prognosis. Various and xenograft models have suggested that attenuating 14-3-3ζ expression may provide therapeutic benefits but there has been no study looking at tumor onset and metastasis in breast cancer mouse models with a targeted deletion of 14-3-3ζ. We generated a 14-3-3ζ knockout mouse model to characterize the role of 14-3-3ζ in breast cancer progression. Crossing 14-3-3ζ-/- mice with MMTV-PyMT and MMTV-Neu transgenic mice revealed that loss of 14-3-3ζ prolonged tumor latency and reduced lung metastasis as compared to MMTV-PyMT and MMTV-Neu mice. Mechanistically, loss of 14-3-3ζ suppressed tumor proliferation and angiogenesis and promoted apoptosis by suppressing the Akt and Erk pathway and upregulated the expression of the tumor suppressor p53. Our results provide evidence showing that attenuating 14-3-3ζ expression/activity in mammary tumors can provide a therapeutic benefit.
14-3-3ζ蛋白属于真核生物调节蛋白的14-3-3家族，该家族通过与多种信号分子结合来调节信号传导。在超过40%的乳腺癌患者中，14-3-3ζ的表达会增强，且这与预后不良相关。各种体外和异种移植模型表明，减弱14-3-3ζ的表达可能具有治疗益处，但尚无研究观察在14-3-3ζ靶向缺失的乳腺癌小鼠模型中的肿瘤发生和转移情况。我们构建了一个14-3-3ζ基因敲除小鼠模型，以研究14-3-3ζ在乳腺癌进展中的作用。将14-3-3ζ基因敲除小鼠与MMTV-PyMT和MMTV-Neu转基因小鼠杂交后发现，与MMTV-PyMT和MMTV-Neu小鼠相比，14-3-3ζ的缺失延长了肿瘤潜伏期并减少了肺转移。从机制上来说，14-3-3ζ的缺失通过抑制Akt和Erk通路来抑制肿瘤增殖和血管生成，并促进细胞凋亡，同时上调肿瘤抑制因子p53的表达。我们的结果提供了证据，表明减弱乳腺肿瘤中14-3-3ζ的表达/活性可带来治疗益处。
