MIR497HG-Derived miR-195 and miR-497 Mediate Tamoxifen Resistance via PI3K/AKT Signaling in Breast Cancer

Sep 24, 2026

Uploaded by Noah

Tamoxifen resistance remains a critical barrier in ER+ breast cancer therapy. This study investigates how the long noncoding RNA MIR497HG and its embedded miR-497/miR-195 regulate tamoxifen response and tumor progression. MIR497HG deficiency drives progression and resistance by downregulating miR-497/195, which coordinately suppresses PI3K-AKT pathway regulators (MAP2K1, AKT3, BCL2, RAF1, and CCND1). PI3K-AKT inhibition restores tamoxifen responsiveness. Mechanistically, ER activates MIR497HG transcription via promoter binding, while ZEB1 recruits HDAC1/2 and DNMT3B to induce promoter hypermethylation and histone deacetylation, linking ZEB1-mediated depletion to PI3K-AKT signaling and resistance. MIR497HG also shows biomarker potential for predicting tamoxifen sensitivity in ER+ patients.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages16

Reading Time40 min

AccessFree to download

Introduction

Tamoxifen use and acquired resistance in ER+ breast cancer

Role of PI3K-AKT signaling in endocrine-resistant disease

Noncoding RNAs and MIR497HG/miR-497/195 background

RESEARCH ARTICLE [www.advancedscience.com](www.advancedscience.com) MIR497HG-Derived miR-195 and miR-497 Mediate Tamoxifen Resistance via PI3K/AKT Signaling in Breast Cancer Yao Tian, Zhao-Hui Chen, Peng Wu, Di Zhang, Yue Ma, Xiao-Feng Liu, Xin Wang, Dan Ding, Xu-Chen Cao,* and Yue Yu* Tamoxifen is commonly used for the treatment of patients with estrogen receptor-positive (ER+) breast cancer, but the acquired resistance to tamoxifen presents a critical challenge of breast cancer therapeutics. Recently, long noncoding RNA MIR497HG and its embedded miR-497 and miR-195 are proved to play signiﬁcant roles in many types of human cancers, but their roles in tamoxifen-resistant breast cancer remain unknown. The results indicate that MIR497HG deﬁciency induces breast cancer progression and tamoxifen resistance by inducing downregulation of miR-497/195. miR-497/195 coordinately represses ﬁve positive PI3K-AKT regulators (MAP2K1, AKT3, BCL2, RAF1, and CCND1), resulting in inhibition of PI3K-AKT signaling, and PI3K-AKT inhibition in tamoxifen-resistant cells restored tamoxifen responsiveness. Furthermore, ER 􀀂 binds the MIR497HG promoter to activate its transcription in an estrogen-dependent manner. ZEB1 interacts with HDAC1/2 and DNMT3B at the MIR497HG promoter, resulting in promoter hypermethylation and histone deacetylation. The ﬁndings reveal that ZEB1-induced MIR497HG depletion contributes to breast cancer progression and tamoxifen resistance through PI3K-AKT signaling. MIR497HG can be used as a biomarker for predicting tamoxifen sensitivity inpatients with ER+ breast cancer. 1. Introduction Breast cancer has surpassed lung cancer in terms of new cases, becoming the most extensively diagnosed cancer in 2020 and the ﬁfth chief cause of cancer death.[1] Nearly 70% of breast cancer patients are estrogen receptor-positive (ER+), making them candidates for endocrine therapies such as tamoxifen, fulvestrant, and letrozole.[2] Tamoxifen, a selective ER modulator, binds to ER competitively and inhibits ER-induced breast cancer cell growth. Asan eﬀective antiestrogenic drug, tamoxifen is extensively used as standard therapy for ER+ breast cancer patients. However, tamoxifen resistance acquisition becomes a signiﬁcant barrier during endocrine therapy.[3] Several biological tamoxifenresistant mechanisms have been reported, including estrogen receptor 1(ESR1) mutation/deletion and other cell proliferation pathways activation, among which, phosphatidylinositol-3-kinase (PI3K) -AKT signaling has been studied most extensively and thoroughly.[4–6] PI3K-AKT signaling is reported to be often activated Y. Tian, Z.-H. Chen, P. Wu, D. Zhang, Y. Ma, X. Wang, X.-C. Cao, Y. Yu The First Department of Breast Cancer Tianjin Medical University Cancer Institute and Hospital National Clinical Research Center for Cancer Tianjin 300060, China E-mail: [caoxuchen@tmu.edu.cn](caoxuchen@tmu.edu.cn); [yuyue@tmu.edu.cn](yuyue@tmu.edu.cn) Y. Tian, Z.-H. Chen, P. Wu, D. Zhang, Y. Ma, X.-F. Liu, X. Wang, X.-C. Cao, Y. Yu Key Laboratory of Cancer Prevention and Therapy Tianjin 300060, China The ORCID identiﬁcation number(s) for the author(s) of this article can be found under [https://doi.org/10.1002/advs.202204819](https://doi.org/10.1002/advs.202204819)[ ](https://doi.org/10.1002/advs.202204819)© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. DOI: 10.1002/advs.202204819 Y. Tian, Z.-H. Chen, P. Wu, D. Zhang, Y. Ma, X.-F. Liu, X. Wang, X.-C. Cao, Y. Yu Tianjin’s Clinical Research Center for Cancer Tianjin 300060, China Y. Tian, Z.-H. Chen, P. Wu, D. Zhang, Y. Ma, X.-F. Liu, X. Wang, X.-C. Cao, Y. Yu Key Laboratory of Breast Cancer Prevention and Therapy Tianjin Medical University Ministry of Education Tianjin 3000

FAQs

How does MIR497HG deficiency affect breast cancer progression and tamoxifen resistance?

MIR497HG deficiency promotes breast cancer progression and induces tamoxifen resistance through downregulation of miR-497/195.

What is the downstream mechanism involving miR-497/195?

miR-497/195 coordinately repress five positive PI3K-AKT regulators (MAP2K1, AKT3, BCL2, RAF1, and CCND1), leading to PI3K-AKT signaling inhibition.

How are MIR497HG transcription and promoter epigenetics regulated?

ER binds the MIR497HG promoter to activate transcription in an estrogen-dependent manner, while ZEB1 interacts with HDAC1/2 and DNMT3B to cause promoter hypermethylation and histone deacetylation.

Sep 24, 2026

Uploaded by Noah