Tumor suppressor DEAR1 regulates mammary epithelial cell fate and predicts early onset and metastasis in triple negative breast cancer.
Tumor suppressor DEAR1 regulates mammary epithelial cell fate and predicts early onset and metastasis in triple negative breast cancer.
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DOI：
10.1038/s41598-022-22417-4
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发表时间：
2022-11-14
影响因子：
4.6
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三阴性乳腺癌（TNBC）是一种预后不良的疾病，大多数被分类为与上皮-间质转化和转移相关的基底细胞样亚型。由于基底乳腺癌起源于增殖性管腔祖细胞样细胞，在适当管腔分化失调时，调节管腔-基底过渡的基因对于阐明改善TNBC结果的新治疗靶点至关重要。在此，我们证明了肿瘤抑制因子DEAR 1/TRIM 62是管腔细胞命运的关键调节因子。人乳腺上皮细胞中的DEAR 1缺失导致显著增强的乳腺球形成，其在TGF-β/SMAD 3信号传导存在下加速。DEAR 1缺失后形成的乳腺球富含ALDH 1A 1和CK 5表达，EpCAM−/CD 49 f+和CD 44 high/24 low基底样上皮细胞，表明DEAR 1调节干/祖细胞特性和管腔-基底祖细胞转换。我们表明，DEAR 1维持管腔分化作为一种新的泛素连接酶的SNAI 2/SLUG，一个主调节驱动干细胞和生成的基底样祖细胞群体。我们还在103例TNBC病例队列中确定了DEAR 1和SNAI 2表达之间的显著负相关性，并表明DEAR 1低表达与发病年龄小和转移时间短显著相关，表明DEAR 1可以作为生物标志物对早发TNBC进行分层，用于靶向干细胞治疗。
Triple negative breast cancer (TNBC) is a disease of poor prognosis, with the majority classified as the basal-like subtype associated with epithelial-mesenchymal transition and metastasis. Because basal breast cancers originate from proliferative luminal progenitor-like cells upon dysregulation of proper luminal differentiation, genes regulating luminal-basal transition are critical to elucidate novel therapeutic targets to improve TNBC outcomes. Herein we demonstrate that the tumor suppressor DEAR1/TRIM62 is a critical regulator of luminal cell fate. DEAR1 loss in human mammary epithelial cells results in significantly enhanced mammosphere formation that is accelerated in the presence of TGF-β/SMAD3 signaling. Mammospheres formed following DEAR1 loss are enriched for ALDH1A1 and CK5 expression, EpCAM−/CD49f+ and CD44high/24low basal-like epithelial cells, indicating that DEAR1 regulates stem/progenitor cell properties and luminal-basal progenitor transition. We show that DEAR1 maintains luminal differentiation as a novel ubiquitin ligase for SNAI2/SLUG, a master regulator driving stemness and generation of basal-like progenitor populations. We also identify a significant inverse correlation between DEAR1 and SNAI2 expression in a 103 TNBC case cohort and show that low DEAR1 expression significantly correlates with young age of onset and shorter time to metastasis, suggesting DEAR1 could serve as a biomarker to stratify early onset TNBCs for targeted stem cell therapies.
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DOI：
10.1186/s13046-016-0445-5
发表时间：
2016-10-28
期刊：
Journal of experimental & clinical cancer research : CR
影响因子：
--
作者：
Liu TY;Chen J;Shang CL;Shen HW;Huang JM;Liang YC;Wang W;Zhao YH;Liu D;Shu M;Guo LY;Hu Z;Yao SZ
通讯作者：
Yao SZ
影响因子：
16.6
作者：
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通讯作者：
Ellisen LW
影响因子：
3.8
作者：
Knudsen, Erik S.;Ertel, Adam;Witkiewicz, Agnieszka K.
通讯作者：
Witkiewicz, Agnieszka K.
DOI：
10.20517/2394-4722.2019.24
发表时间：
2019-01-01
期刊：
Journal of cancer metastasis and treatment
影响因子：
--
作者：
Anstine, Lindsey J;Keri, Ruth
通讯作者：
Keri, Ruth
影响因子：
4.6
作者：
Li W;Ma H;Zhang J;Zhu L;Wang C;Yang Y
通讯作者：
Yang Y