靶向 LRP8 抑制三阴性乳腺癌中的乳腺癌干细胞。
Targeting LRP8 inhibits breast cancer stem cells in triple-negative breast cancer.
机构信息
Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI, 48109, USA.
Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI, 48109, USA.
出版信息
Cancer Lett. 2018 Dec 1;438:165-173. doi: 10.1016/j.canlet.2018.09.022. Epub 2018 Sep 15.
Abstract
Triple-negative breast cancer (TNBC) is the most difficult subtype of breast cancer to treat due to a paucity of effective targeted therapies. Many studies have reported that breast cancer stem cells (BCSCs) are enriched in TNBC and are responsible for chemoresistance and metastasis. In this study, we identify LRP8 as a novel positive regulator of BCSCs in TNBC. LRP8 is highly expressed in TNBC compared to other breast cancer subtypes and its genomic locus is amplified in 24% of TNBC tumors. Knockdown of LRP8 in TNBC cell lines inhibits Wnt/β-catenin signaling, decreases BCSCs, and suppresses tumorigenic potential in xenograft models. LRP8 knockdown also induces a more differentiated, luminal-epithelial phenotype and thus sensitizes the TNBC cells to chemotherapy. Together, our study highlights LRP8 as a novel therapeutic target for TNBC as inhibition of LRP8 can attenuate Wnt/β-catenin signaling to suppress BCSCs.
摘要
三阴性乳腺癌（TNBC）是最难治疗的乳腺癌亚型，因为缺乏有效的靶向治疗方法。许多研究报告称，乳腺癌干细胞（BCSCs）在 TNBC 中富集，并负责化疗耐药和转移。在这项研究中，我们确定 LRP8 是 TNBC 中 BCSCs 的新型正调控因子。LRP8 在 TNBC 中比其他乳腺癌亚型表达更高，其基因组位点在 24%的 TNBC 肿瘤中扩增。在 TNBC 细胞系中敲低 LRP8 可抑制 Wnt/β-catenin 信号通路，减少 BCSCs，并抑制异种移植模型中的肿瘤发生潜能。LRP8 敲低还诱导更分化的腔上皮表型，从而使 TNBC 细胞对化疗更敏感。总之，我们的研究强调了 LRP8 作为 TNBC 的一个新的治疗靶点，因为抑制 LRP8 可以减弱 Wnt/β-catenin 信号通路，从而抑制 BCSCs。
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本文引用的文献
1
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Cancer Res. 2018 Aug 1;78(15):4191-4202. doi: 10.1158/0008-5472.CAN-18-0270. Epub 2018 Jun 7.
2
Wnt/β-Catenin Signaling, Disease, and Emerging Therapeutic Modalities.Wnt/β-连环蛋白信号通路、疾病与新兴治疗模式。
Cell. 2017 Jun 1;169(6):985-999. doi: 10.1016/j.cell.2017.05.016.
3
miRpower: a web-tool to validate survival-associated miRNAs utilizing expression data from 2178 breast cancer patients.miRpower：一种利用2178例乳腺癌患者的表达数据来验证与生存相关的微小RNA的网络工具。
Breast Cancer Res Treat. 2016 Dec;160(3):439-446. doi: 10.1007/s10549-016-4013-7. Epub 2016 Oct 15.
4
EMT: 2016.EMT：2016 年。
Cell. 2016 Jun 30;166(1):21-45. doi: 10.1016/j.cell.2016.06.028.
5
Triple-negative breast cancer: challenges and opportunities of a heterogeneous disease.三阴性乳腺癌：一种异质性疾病的挑战与机遇
Nat Rev Clin Oncol. 2016 Nov;13(11):674-690. doi: 10.1038/nrclinonc.2016.66. Epub 2016 May 17.
6
Activation of PKA leads to mesenchymal-to-epithelial transition and loss of tumor-initiating ability.蛋白激酶A的激活会导致间充质向上皮转化以及肿瘤起始能力的丧失。
Science. 2016 Mar 4;351(6277):aad3680. doi: 10.1126/science.aad3680.
7
Clinical implications of the intrinsic molecular subtypes of breast cancer.乳腺癌内在分子亚型的临床意义。
Breast. 2015 Nov;24 Suppl 2:S26-35. doi: 10.1016/j.breast.2015.07.008. Epub 2015 Aug 5.
8
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Neuron. 2015 May 6;86(3):696-710. doi: 10.1016/j.neuron.2015.03.033. Epub 2015 Apr 16.
9
β-Catenin is required for the tumorigenic behavior of triple-negative breast cancer cells.β-连环蛋白是三阴性乳腺癌细胞致瘤行为所必需的。
PLoS One. 2015 Feb 6;10(2):e0117097. doi: 10.1371/journal.pone.0117097. eCollection 2015.
10
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Proc Natl Acad Sci U S A. 2014 Dec 16;111(50):E5429-38. doi: 10.1073/pnas.1421438111. Epub 2014 Dec 1.
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