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Sox2-Sox9 信号轴维持人乳腺腔前体细胞和乳腺癌干细胞。

A Sox2-Sox9 signalling axis maintains human breast luminal progenitor and breast cancer stem cells.

机构信息

CIC bioGUNE, Technological Park Bizkaia, Derio, 48160, Spain.

The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK.

出版信息

Oncogene. 2019 Apr;38(17):3151-3169. doi: 10.1038/s41388-018-0656-7. Epub 2019 Jan 8.

DOI:10.1038/s41388-018-0656-7
PMID:30622340
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6756022/
Abstract

Increased cancer stem cell content during development of resistance to tamoxifen in breast cancer is driven by multiple signals, including Sox2-dependent activation of Wnt signalling. Here, we show that Sox2 increases and estrogen reduces the expression of the transcription factor Sox9. Gain and loss of function assays indicate that Sox9 is implicated in the maintenance of human breast luminal progenitor cells. CRISPR/Cas knockout of Sox9 reduces growth of tamoxifen-resistant breast tumours in vivo. Mechanistically, Sox9 acts downstream of Sox2 to control luminal progenitor cell content and is required for expression of the cancer stem cell marker ALDH1A3 and Wnt signalling activity. Sox9 is elevated in breast cancer patients after endocrine therapy failure. This new regulatory axis highlights the relevance of SOX family transcription factors as potential therapeutic targets in breast cancer.

摘要

在乳腺癌对他莫昔芬耐药性发展过程中，癌症干细胞含量的增加是由多种信号驱动的，包括 Sox2 依赖性激活 Wnt 信号通路。在这里，我们表明 Sox2 增加，而雌激素降低转录因子 Sox9 的表达。获得和丧失功能实验表明 Sox9 参与维持人乳腺腔前体细胞。CRISPR/Cas 敲除 Sox9 减少体内他莫昔芬耐药性乳腺肿瘤的生长。从机制上讲，Sox9 作为 Sox2 的下游因子来控制腔前体细胞的含量，并且是癌症干细胞标志物 ALDH1A3 和 Wnt 信号活性表达所必需的。在内分泌治疗失败的乳腺癌患者中 Sox9 升高。这个新的调控轴突出了 SOX 家族转录因子作为乳腺癌潜在治疗靶点的相关性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4800/6756022/41890991c6da/41388_2018_656_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4800/6756022/62cb88498b1c/41388_2018_656_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4800/6756022/48defbe18014/41388_2018_656_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4800/6756022/843764bd69ed/41388_2018_656_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4800/6756022/a49343ffc1bc/41388_2018_656_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4800/6756022/1164b4866482/41388_2018_656_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4800/6756022/c022f7482cf8/41388_2018_656_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4800/6756022/5162203ccdfd/41388_2018_656_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4800/6756022/41890991c6da/41388_2018_656_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4800/6756022/62cb88498b1c/41388_2018_656_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4800/6756022/48defbe18014/41388_2018_656_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4800/6756022/843764bd69ed/41388_2018_656_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4800/6756022/a49343ffc1bc/41388_2018_656_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4800/6756022/1164b4866482/41388_2018_656_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4800/6756022/c022f7482cf8/41388_2018_656_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4800/6756022/5162203ccdfd/41388_2018_656_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4800/6756022/41890991c6da/41388_2018_656_Fig8_HTML.jpg

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