HAS2-Ezrin-ER axis plays a role in acquired antiestrogen resistance of ER-positive breast cancer.
HAS2-Ezrin-ER axis plays a role in acquired antiestrogen resistance of ER-positive breast cancer.
复制标题
DOI：
10.3389/fphar.2022.1031487
复制
发表时间：
2022
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
--
作者：
内分泌耐药的发展是雌激素受体阳性（ER+）乳腺癌（BrCa）治疗中的一个主要临床问题，其中癌细胞如何获得耐药尚不清楚。透明质酸合成酶2 （Hyaluronan synthase 2, HAS2）是产生透明质酸最关键的合成酶，因其参与肿瘤的生长、代谢和转移而闻名。最近的证据证明，HAS2参与BrCa的细胞获得性耐药治疗。在这项工作中，我们首先观察到HAS2在内分泌抗性ER+ BrCa细胞中的表达降低。进一步的敲除实验证实，亲代ER+ BrCa细胞中HAS2的缺失导致了随后的抗雌激素抵抗。接下来，我们发现has2缺失可以诱导Ezrin上调，Ezrin是膜细胞骨架蛋白家族的一员，在细胞信号转导中起关键作用。值得注意的是，我们发现has2缺失引起的Ezrin增加可以抑制ERα表达并增强抗雌激素抵抗，这表明HAS2-Ezrin-ER轴可能与ER+ BrCa细胞获得内分泌抵抗有关。最后，敲低或抑制Ezrin可通过激活ERα信号通路恢复内分泌抵抗细胞对抗雌激素治疗的敏感性。综上所述，我们的研究结果揭示了一种新的HAS2-Ezrin-ER途径在调节ER+ BrCa细胞对抗雌激素的敏感性方面，其中Ezrin可能是内分泌治疗的潜在靶点。
The development of endocrine resistance is a major clinical problem in estrogen receptor-positive (ER+) breast cancer (BrCa) treatment, in which how cancer cells acquire resistance remains obscure. Hyaluronan synthase 2 (HAS2) is the most critical synthase in producing hyaluronan and is well known for its involvement in cancer growth, metabolism and metastasis. Recent evidence has proved that HAS2 is involved in cellular acquired resistance to drug therapy in BrCa. In this work, we first observed that HAS2 expression was decreased in the endocrine-resistant ER+ BrCa cells. Further knocking-out experiments confirmed that the loss of HAS2 in parental ER+ BrCa cells resulted in a following antiestrogen resistance. Next, we found that the HAS2-loss could induce an upregulation of Ezrin, a member of the membrane cytoskeletal protein family who plays key roles in cellular signal transduction. Notably, we identified that the increase of Ezrin induced by HAS2-loss could inhibit the ERα expression and augment antiestrogen resistance, suggesting that a HAS2-Ezrin-ER axis may be associated with the acquirement of endocrine resistance in ER+ BrCa cells. Finally, knockdown or inhibition of Ezrin could restore the sensitivity of endocrine-resistant cells to antiestrogens treatment by activating ERα signaling. Taken together, our findings unraveled a novel HAS2-Ezrin-ER route in regulating the sensitivity of ER+ BrCa cells to antiestrogens, in which Ezrin may be a potential target in endocrine therapy.
登录
查看更多内容
影响因子：
5.5
作者：
Fallah Y;Brundage J;Allegakoen P;Shajahan-Haq AN
通讯作者：
Shajahan-Haq AN
影响因子：
8
作者：
Thrane, S.;Pedersen, A. M.;Yde, C. W.
通讯作者：
Yde, C. W.
影响因子：
4.8
作者：
Saygideger-Kont, Yasemin;Minas, Tsion Zewdu;Jones, Hayden;Hour, Sarah;Celik, Haydar;Temel, Idil;Han, Jenny;Atabey, Nese;Erkizan, Hayriye Verda;Toretsky, Jeffrey A.;Uren, Aykut
通讯作者：
Uren, Aykut
DOI：
10.1073/pnas.0407113102
发表时间：
2005-01-18
影响因子：
11.1
作者：
Cheung, E;Acevedo, ML;Kraus, WL
通讯作者：
Kraus, WL
DOI：
10.1126/science.aah6893
发表时间：
2017-03-24
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Toska E;Osmanbeyoglu HU;Castel P;Chan C;Hendrickson RC;Elkabets M;Dickler MN;Scaltriti M;Leslie CS;Armstrong SA;Baselga J
通讯作者：
Baselga J