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HAS2-Ezrin-ER axis plays a role in acquired antiestrogen resistance of ER-positive breast cancer

Authors :
Xiaodan Sun
Fen Tang
Qian Guo
Yiwen Liu
Yiqing He
Yan Du
Feng Gao
Guoliang Zhang
Cuixia Yang
Source :
Frontiers in Pharmacology, Vol 13 (2022)
Publication Year :
2022
Publisher :
Frontiers Media S.A., 2022.

Abstract

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.

Details

Language :
English
ISSN :
16639812
Volume :
13
Database :
Directory of Open Access Journals
Journal :
Frontiers in Pharmacology
Publication Type :
Academic Journal
Accession number :
edsdoj.3dcd0dc1acc740ad9aacd0bb66f74ad3
Document Type :
article
Full Text :
https://doi.org/10.3389/fphar.2022.1031487