Targeting estrogen-regulated system xc− promotes ferroptosis and endocrine sensitivity of ER+ breast cancer

Sep 23, 2026

Uploaded by Finn

ERα signaling restrains ferroptosis and contributes to endocrine resistance in estrogen receptor-positive (ER+) breast cancer. The study identifies ERα as transcriptionally upregulating SLC7A11 and SLC3A2, the key subunits of the system xc− axis that limits ferroptosis by controlling redox homeostasis. ERα silencing triggers ferroptosis, suppressible by Ferrostatin-1 and potentiated by Erastin, while restoring SLC7A11/SLC3A2 counteracts this effect. System xc− inhibition by Sorafenib or imidazole ketone erastin blocks tamoxifen-resistant growth in vitro and in vivo, supporting a therapeutic option for endocrine-resistant disease.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages14

Reading Time35 min

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Introduction

Estrogen signaling and endocrine resistance in ER+ breast cancer

Ferroptosis and the system xc−–GPX4 axis

[www.nature.com/cddis](www.nature.com/cddis) ARTICLE OPEN Targeting estrogen-regulated system xc − promotes ferroptosisand endocrine sensitivity of ER+ breast cancer Jiawei Cao 1,5 ✉ , Tong Zhou1,5, Tao Wu1, Rixu Lin2, Ju Huang 1, Dejin Shi1, Jiawei Yu1, Yinrui Ren1, Changrui Qian3, Licai He1, Guang Wu1, Zhixiong Dong 1, Shaofei Yuan4 ✉ and Haihua Gu 1 ✉ © The Author(s) 2025 | | Estrogen receptor positive (ER+) breast cancer accounts for approximately 70% of cases. Endocrine therapies targeting estrogen are the ﬁrst line therapies for ER+ breast cancer. However, resistance to these therapies occurs in about half of patients, leading to decreased survival rates. Inducing ferroptosis is a promising therapeutic strategy for cancer treatment for refractory and malignant cancers including triple-negative breast cancer. Nevertheless, ER+ breast cancer is relatively resistant to ferroptosis inducers. Here, we uncovered that ERα suppressed ferroptosis in ER+ breast cancer. Silencing ERα triggered ferroptosis, which was attenuated by ferroptosis inhibitor Ferrostatin-1, and was enhanced by ferroptosis inducer Erastin. Mechanistically, ERα transcriptionally upregulated the expression of SLC7A11 and SLC3A2, two subunits of the system xc − , which is one key inhibitory regulator offerroptosis. Overexpression of the exogenous SLC7A11 and SLC3A2 was able to mitigate ferroptosis induced by ERα inhibition. Moreover, SLC7A11 and SLC3A2 levels were elevated in endocrine-resistant breast cancer cells and tumors. Importantly, the system xc − inhibitor Sorafenib or Imidazole ketone erastin effectively inhibited the growth of tamoxifen-resistant breast cells in vitro and in vivo. In conclusion, our data reveal that targeting estrogen-regulated SLC7A11 and SLC3A2 enhances ferroptosis in ER+ breast | | | --- | --- | --- | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | cancer, offering a novel therapeutic option for patients with ER+ breast cancer, particularly those with endocrine resistance. | | | | | Cell Death and Disease (2025)16:30; [https://doi.org/10.1038/s41419-025-07354-0](https://doi.org/10.1038/s41419-025-07354-0) | | | | | | INTRODUCTION Surpassing lung cancer, breast cancer has emerged as the foremost type of cancer globally [1] . Estrogen receptor positive (ER+) breast cancer constitutes approximately 70% of all breast cancer cases, relying on estrogen for its growth [2, 3]. ERα, a steroid hormone receptor processing a multifunctional domain, serves as the principal driver of ER+ breast cancer by acting primarily as a transcription factor. Upon binding to estrogen, ERα translocates to the nucleus where it binds to DNA regions containing estrogenresponsive elements (ERE) and subsequently regulates the transcription of numerous genes that are crucial for breast tumorigenesis [4] . Anti-estrogen-based endocrine therapies, such as the ERα modulator Tamoxifen, ERα degrader Fulvestrant, and the aromatase inhibitor Letrozole, have signiﬁcantly enhanced the survival rates of patients with hormone receptor-positive (HR+) breast cancer [5] . However, approximately half of the patients undergoing endocrine therapy suffer relapses, including mutations in the ERα coding gene ESR1, especially the L536Q and Y537S mutations [6], which present a signiﬁcant clinical challenge. Ferroptosis, a form of regulated cell death identiﬁed in 2012 [7], differs from other forms of regulated cell death such as apoptosis and pyroptosis, as well as necrosis. Ferroptosis occurs due to its iron-dependent catalysis of lipid peroxidation, leading to the accumulation of lipid peroxides (lipid ROS) in cell membranes and the subsequent cell demise [8, 9]. System xc − -GPX4 axis plays a critical role in regulating ferroptosis by maintaining cellular redox homeostasis and alleviating oxidative stress. System xc − functions as an amino acid antiporter that consists of the light chain SL

FAQs

Why is endocrine therapy less effective in ER+ breast cancer?

About half of patients experience relapses during endocrine therapy, including cases involving ESR1 mutations such as L536Q and Y537S, which increases clinical resistance.

How does ERα influence ferroptosis in ER+ breast cancer?

ERα suppresses ferroptosis by transcriptionally increasing SLC7A11 and SLC3A2, subunits of the system xc− axis that helps inhibit ferroptosis through redox regulation.

What is the therapeutic rationale for targeting system xc−?

Inhibitors of system xc− such as Sorafenib or imidazole ketone erastin effectively inhibit growth of tamoxifen-resistant breast cells in vitro and in vivo, offering a potential strategy for endocrine-resistant ER+ breast cancer.

Sep 23, 2026

Uploaded by Finn