miR-489 Confines Uncontrolled Estrogen Signaling through a Negative Feedback Mechanism and Regulates Tamoxifen Resistance in Breast Cancer.
miR-489 Confines Uncontrolled Estrogen Signaling through a Negative Feedback Mechanism and Regulates Tamoxifen Resistance in Breast Cancer.
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miR - 489通过负反馈机制限制不受控制的雌激素信号传导，并调节乳腺癌中的他莫昔芬耐药性。
DOI：
10.3390/ijms23158086
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发表时间：
2022-07-22
影响因子：
5.6
通讯作者：
Chen, Hexin
中科院分区：
文献类型：
--
作者：
Soni, Mithil;Saatci, Ozge;Gupta, Gourab;Patel, Yogin;Raja, Manikanda Raja Keerthi;Li, Jie;Liu, Xinfeng;Xu, Peisheng;Wang, Hongjun;Fan, Daping;Sahin, Ozgur;Chen, Hexin
大约75%已确诊的乳腺癌肿瘤为雌激素受体阳性肿瘤，由于对激素疗法有反应，其预后较好。然而，约40%的患者在激素治疗后复发。对原发性乳腺癌和他莫昔芬耐药细胞系的基因表达谱进行的基因组分析表明，miR - 489在雌激素信号调节和他莫昔芬耐药性产生中具有潜在作用。我们的体外分析显示，miR - 489表达缺失促进了他莫昔芬耐药，而在他莫昔芬耐药细胞中过表达miR - 489则恢复了他莫昔芬敏感性。从机制上讲，我们发现miR - 489是一种受雌激素调节的微小RNA，它通过至少以下两种机制对雌激素受体信号传导进行负向调节：（i）通过抑制MAPK和AKT激酶活性来调节雌激素受体（ER）的磷酸化状态；（ii）通过降低p38表达并进而调节雌激素受体α（ERα）的磷酸化来调控雌激素受体α从细胞核到细胞质的易位。此外，miR - 489可以打破乳腺癌细胞中雌激素 - ERα轴和p38 MAPK之间的正向前馈环路，这对其作为转录因子的功能是必要的。总体而言，我们的研究揭示了miR - 489通过负反馈环路调节雌激素信号通路的潜在分子机制，并揭示了其在乳腺癌他莫昔芬耐药性产生和克服中的作用。
Approximately 75% of diagnosed breast cancer tumors are estrogen-receptor-positive tumors and are associated with a better prognosis due to response to hormonal therapies. However, around 40% of patients relapse after hormonal therapies. Genomic analysis of gene expression profiles in primary breast cancers and tamoxifen-resistant cell lines suggested the potential role of miR-489 in the regulation of estrogen signaling and development of tamoxifen resistance. Our in vitro analysis showed that loss of miR-489 expression promoted tamoxifen resistance, while overexpression of miR-489 in tamoxifen-resistant cells restored tamoxifen sensitivity. Mechanistically, we found that miR-489 is an estrogen-regulated miRNA that negatively regulates estrogen receptor signaling by using at least the following two mechanisms: (i) modulation of the ER phosphorylation status by inhibiting MAPK and AKT kinase activities; (ii) regulation of nuclear-to-cytosol translocation of estrogen receptor α (ERα) by decreasing p38 expression and consequently ER phosphorylation. In addition, miR-489 can break the positive feed-forward loop between the estrogen-Erα axis and p38 MAPK in breast cancer cells, which is necessary for its function as a transcription factor. Overall, our study unveiled the underlying molecular mechanism by which miR-489 regulates an estrogen signaling pathway through a negative feedback loop and uncovered its role in both the development of and overcoming of tamoxifen resistance in breast cancers.
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影响因子：
11.5
作者：
Miller, Philip C.;Clarke, Jennifer;El-Ashry, Dorraya
通讯作者：
El-Ashry, Dorraya
影响因子：
45.3
作者：
Gutierrez, MC;Detre, S;Dowsett, M
通讯作者：
Dowsett, M
DOI：
10.1073/pnas.0906947106
发表时间：
2009-09-15
影响因子：
11.1
作者：
Castellano, Leandro;Giamas, Georgios;Stebbing, Justin
通讯作者：
Stebbing, Justin
影响因子：
8
作者：
Lo, P-K;Kanojia, D.;Liu, X.;Singh, U. P.;Berger, F. G.;Wang, Q.;Chen, H.
通讯作者：
Chen, H.
影响因子：
--
作者：
Frigo, DE;Basu, A;Burow, ME
通讯作者：
Burow, ME