RAD51AP1 Deficiency Reduces Tumor Growth by Targeting Stem Cell Self-Renewal.
RAD51AP1 Deficiency Reduces Tumor Growth by Targeting Stem Cell Self-Renewal.
复制标题
DOI：
10.1158/0008-5472.can-19-3713
复制
发表时间：
2020-09-15
期刊：
影响因子：
11.2
通讯作者：
中科院分区：
文献类型：
--
作者：
RAD51AP1 （RAD51-associated protein 1）通过激活RAD51重组酶在同源重组（homologous recombination， HR）中发挥重要作用。HR对于保持基因组完整性至关重要，RAD51AP1对于D-loop的形成至关重要，D-loop是HR的关键步骤。虽然RAD51AP1参与维持基因组稳定性，但最近的研究表明，RAD51AP1在人类癌症中表达显著上调。然而，RAD51AP1在肿瘤生长中的功能作用以及RAD51AP1调控肿瘤发生的潜在分子机制尚不完全清楚。我们在乳腺癌基因工程小鼠（GEM）模型中使用Rad51ap1敲除小鼠，以揭示Rad51ap1在肿瘤生长和转移中的作用。RAD51AP1基因转录在腔内雌激素受体阳性乳腺癌（ER+BC）和基底三阴性乳腺癌（TNBC）中均升高，与预后不良相关。相反，在乳腺癌细胞系中，RAD51AP1 （RADP51AP1 KD）的敲低会降低肿瘤的生长。rad51ap1缺陷小鼠可免受癌基因驱动的自发性小鼠乳腺肿瘤生长和相关肺转移的影响。在体内，限制性稀释研究提供了Rad51ap1在乳腺癌干细胞（BCSC）自我更新中起关键作用的证据。RAD51AP1 KD通过抑制BCSC自我更新和相关多能性改善化疗和放疗反应。总之，我们的研究提供了遗传和生化证据，表明RAD51AP1通过增加BCSC干细胞的自我更新对肿瘤生长和转移至关重要，并可能成为化疗和放疗耐药乳腺癌的新靶点。
RAD51AP1 (RAD51-associated protein 1) plays an integral role in homologous recombination (HR) by activating RAD51 recombinase. HR is essential for preserving genome integrity and RAD51AP1 is critical for D-loop formation, a key step in HR. Although RAD51AP1 is involved in maintaining genomic stability, recent studies have shown that RAD51AP1 expression is significantly upregulated in human cancers. However, the functional role of RAD51AP1 in tumor growth and the underlying molecular mechanism(s) by which RAD51AP1 regulates tumorigenesis have not been fully understood. Here we use Rad51ap1 knockout mice in genetically engineered mouse (GEM) models of breast cancer to unravel the role of RAD51AP1 in tumor growth and metastasis. RAD51AP1 gene transcript was increased in both luminal estrogen receptor-positive breast cancer (ER+BC) and basal triple-negative breast cancer (TNBC), which is associated with a poor prognosis. Conversely, knockdown of RAD51AP1 (RADP51AP1 KD) in breast cancer cell lines reduced tumor growth. Rad51ap1-deficient mice were protected from oncogene-driven spontaneous mouse mammary tumor growth and associated lung metastasis. In vivo, limiting dilution studies provided evidence that Rad51ap1 plays a critical role in breast cancer stem cell (BCSC) self-renewal. RAD51AP1 KD improved chemotherapy and radiation therapy response by inhibiting BCSC self-renewal and associated pluripotency. Overall, our study provides genetic and biochemical evidences that RAD51AP1 is critical for tumor growth and metastasis by increasing BCSC stem cell self-renewal and may serve as a novel target for chemotherapy- and radiation therapy-resistant breast cancer.