Human iPSC-based breast cancer model identifies S100P-dependent cancer stemness induced by BRCA1 mutation

IF 12.5 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Advances Pub Date : 2025-07-25 DOI:10.1126/sciadv.adi2370

Jingxin Liu, Cai Zhao, Jiahao Chen, Pengguihang Zeng, Qingjian Li, Ranran Dai, Xingqiang Lai, Wenqian Song, Jianing Chen, Xixi Zhu, Xinyi Liu, Jun Sun, Jia Wang, Peihang Fang, Tengfei Wang, Wenjie Chen, Diana Guallar, Nan Cao, Jianli Zhao, Shicheng Su, Andy Peng Xiang, Yi Arial Zeng, Jie Li, Junchao Cai, Dung-Fang Lee, Jinxin Bei, Yongliang Huo, Hai Hu, Shengbao Suo, Dong-feng Huang, Jin Bai, Junjun Ding

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Abstract

Breast cancer is the most common malignancy in females and remains the leading cause of cancer-related deaths for women worldwide. The cellular and molecular basis of breast tumorigenesis is not completely understood partly due to the lack of human research models which simulate the development of breast cancer. Here, we developed a method for generating functional mammary-like cells (MCs) from human-induced pluripotent stem cells (iPSCs). The iPSC-MCs closely resemble human primary MCs at cellular, transcriptional, and functional levels. Using this method, a breast cancer model was generated using patient-derived iPSCs harboring germline BRCA1 mutation. The patient iPSC-MCs recapitulated the transcriptome, clinical genomic alteration, and tumorigenic ability of breast cancer cells. We also identified S100P as an oncogene downstream of mutated BRCA1 that promotes cancer cell stemness and tumorigenesis. Our study establishes a promising system of breast cancer for studying the mechanism of tumorigenesis and identifying potential therapeutic targets.

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基于人类ipsc的乳腺癌模型鉴定BRCA1突变诱导的s100p依赖性癌症干性

乳腺癌是女性中最常见的恶性肿瘤，并且仍然是全世界妇女癌症相关死亡的主要原因。乳腺肿瘤发生的细胞和分子基础尚未完全了解，部分原因是缺乏模拟乳腺癌发展的人类研究模型。在这里，我们开发了一种从人类诱导的多能干细胞（iPSCs）中生成功能性乳腺样细胞（MCs）的方法。iPSC-MCs在细胞、转录和功能水平上与人类原代MCs非常相似。利用这种方法，利用携带种系BRCA1突变的患者来源的iPSCs生成了乳腺癌模型。患者iPSC-MCs重现了乳腺癌细胞的转录组、临床基因组改变和致瘤能力。我们还发现S100P是突变BRCA1下游的致癌基因，可促进癌细胞干性和肿瘤发生。我们的研究为研究肿瘤发生机制和确定潜在的治疗靶点建立了一个有前景的乳腺癌系统。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Science Advances 综合性期刊-综合性期刊

CiteScore

21.40

自引率

1.50%

发文量

1937

审稿时长

29 weeks

期刊介绍： Science Advances, an open-access journal by AAAS, publishes impactful research in diverse scientific areas. It aims for fair, fast, and expert peer review, providing freely accessible research to readers. Led by distinguished scientists, the journal supports AAAS's mission by extending Science magazine's capacity to identify and promote significant advances. Evolving digital publishing technologies play a crucial role in advancing AAAS's global mission for science communication and benefitting humankind.