Li et al. Biomarker Research (2020) 8:58 https://doi.org/10.1186/s40364-020-00230-3 REVIEW Open Access Targeting ferroptosis in breast cancer Zhaoqing Li1,2,3†,LiniChen1,3†,CongChen1,3†,YuluZhou1,3, Dengdi Hu4, Jingjing Yang1,3,YongxiaChen1,3, Wenying Zhuo4,MishaMao1,3,XunZhang1,3,LingXu1,3,LinboWang1,3* and Jichun Zhou1,3* Abstract Ferroptosis is a recently discovered distinct type of regulated cell death caused by the accumulation of lipid-based ROS. Metabolism and expression of specific genes affect the occurrence of ferroptosis, making it a promising therapeutic target to manage cancer. Here, we describe the current status of ferroptosis studies in breast cancer and trace the key regulators of ferroptosis back to previous studies. We also compare ferroptosis to common regulated cell death patterns and discuss the sensitivity to ferroptosis in different subtypes of breast cancer. We propose that viewing ferroptosis-related studies from a historical angle will accelerate the development of ferroptosis-based biomarkers and therapeutic strategies in breast cancer. Keywords: Ferroptosis, Breast cancer, Regulated cell death, Crosstalk, Ferroptotic regulators, Historical perspective Introduction active iron and loss of lipid peroxide repairing ability [3]. Breast cancer is the most common cancer among Numerous agents targeting corresponding molecules women, with 1.7 million people diagnosed worldwide involved in ferroptosis have been developed, making it a and approximately half a million people deaths from this promising therapeutic strategy for cancer. Although a disease each year [1]. Although surgical resection, radio- definitive pathophysiological function of ferroptosis has therapy, chemotherapy, endocrine therapy and targeted yet to be clearly demonstrated, the roles of ferroptosis in therapy have been applied for treatment, the prognosis human diseases have been established, such as neuro- of patients with breast cancer is still not satisfactory [2]. degeneration [6, 7], ischaemia reperfusion injury [8] and Therefore, there is an urgent need to develop novel various kinds of cancer including breast cancer [9–12]. therapeutic management for these patients who require A wealth of studies have suggested that pharmacological more precise intervention. modulation of this unique cell death modality, either by The term ferroptosis was coined in 2012 to describe inhibiting or stimulating it, may yield significant clinical an iron-dependent regulated form of cell death caused benefit for certain diseases. by the accumulation of lipid-based reactive oxygen spe- Accumulating evidence indicates that ferroptotic cell cies (ROS) [3, 4]. Morphologically, obvious shrinkage of death leads to tumour growth suppression. Targeting mitochondria with an increased membrane density and ferroptosis might be a promising anticancer strategy. Re- reduction of mitochondrial cristae could be observed, cent discoveries of ferroptosis-inducing agents and fur- distinguishing ferroptosis from other types of cell death, ther identification of regulatory mechanisms and genes such as apoptosis, autophagy, and necrosis [5]. Ferropto- involved in ferroptosis serve as a foundation for develop- sis is characterized by oxidation of polyunsaturated fatty ing strategies for targeting ferroptosis in cancer therapy. acid-containing phospholipids, the presence of redox- Therefore, a better understanding of the processes that regulate ferroptosis sensitivity should ultimately aid in * Correspondence: [email protected]; [email protected] the discovery of novel therapeutic strategies to improve †Zhaoqing Li, Lini Chen and Cong Chen contributed equally to this work. 1Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang cancer treatment. University, Hangzhou 310000, Zhejiang, China Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Li et al. Biomarker Research (2020) 8:58 Page 2 of 27 Although ferroptosis was defined only a few years from other types of cell death. Ferroptosis does not in- prior, traces of its existence have emerged in previous duce chromatin agglutination or apoptotic bodies forma- studies in the last several decades. In this review, we first tion that occur in apoptosis, or plasma membrane briefly introduce the main characteristics of ferroptosis breakdown that occurs in necroptosis, or formation of and compare it with the other four common types of double-membraned autolysosomes that occurs in au- regulated cell death. We then discuss the current status tophagy, or rupture of plasma membrane that occurs in of ferroptosis-related studies in breast cancer and differ- pyroptosis; instead, it results in mitochondrial shrinkage ences between different subtypes of breast cancer, along and increased mitochondrial membrane density [4, 61]. with an extensive historical study consistent with the Ferroptosis also has its unique biochemical features such current definition of ferroptosis in breast cancer. From a as iron accumulation, lipid peroxidation, and elevated historical perspective, we discuss recent implications and ΔΨm. Numerous small molecules inducing ferroptosis applications of manipulations of the ferroptotic death have been identified and divided into 5 classes. Class I pathway in breast cancer. FINs deplete GSH to inactivate GPX4; class II and III FINs inactivate GPX4 directly; class IV FINs induce iron What is ferroptosis? overload; and others induce ferroptosis via other mecha- From 2001 to 2003, the Stockwell Lab performed a nisms. Ferroptosis inhibitors are divided as iron chela- screen to identify compounds that kill cells tors, anti-oxidants, ROS formation inhibitors and others engineered to be tumourigenic (harbouring the RAS [5, 19, 22, 69, 71]. The main morphological features, mutant), without killing their isogenic parental pre- regulating genes, inducers and inhibitors of ferroptosis, cursors. One of the most efficient compounds was apoptosis, necroptosis, pyroptosis and autophagy- identified and named “erastin” after its ability to dependent cell death are listed in Table 1. “Eradicate RAS-and Small T transformed cells” [13]. Ferroptosis has been considered to be involved in mul- Subsequently, they identified RSL3, which was also tiple pathological processes according to current studies named after its “oncogenic-RAS-selective lethal” prop- (shown in Fig. 2)[5, 72, 73]. For instance, it is linked to erty in 2008 [14]. In 2012, the term “ferroptosis” was ischaemia reperfusion injury (IRI) in liver, heart and kid- coined to describe this iron-dependent, non-apoptotic ney and neurodegenerative diseases such as Alzheimer’s form of cell death induced by erastin and RSL3 [4]. disease, Parkinson’s disease and Huntington’s disease As ferroptosis became the focus of scientific research, [74, 75]. Other diseases such as liver fibrosis, stroke, type an increasing number of mechanisms have been re- 1 diabetes, atherosclerosis and acute kidney injury are vealed. Three hallmarks of ferroptosis were described also associated with ferroptosis [8]. With the new con- by Stockwell et al., i.e., the loss of lipid peroxide cept of ferroptosis, our cognition of the mechanism of repair capacity by the phospholipid hydroperoxidase many diseases may be changed. Furthermore, ferroptosis glutathione peroxidase-4 (GPX4), the availability of is observed in various types of cancer, including breast redox-active iron, and oxidation of polyunsaturated [12], gastric [11], lung [76], and pancreatic cancer [9], fatty acid (PUFA)-containing phospholipids [3], among others, providing a novel method to treat malig- among which the latter is the main driver of ferropto- nancies [24]. tic death [15]. Thus, molecules that regulate the above processes may induce or suppress ferroptosis. Current status of ferroptosis studies in breast For example, SLC7A11 (xCT), a subunit of system cancer xc-, has been considered to be one of the most im- Breast cancer can be divided into several types, including portant regulators of ferroptosis by importing cysteine luminal A/B, HER-2 enriched, basal-like and normal-like to synthesise GSH, which is the enzyme co-substrate subtypes. According to NCCN guidelines, endocrine of GPX4 in the conversion of lipid hydroperoxides to therapy is used for ER-positive breast cancer and anti- lipid alcohol [3]. NCOA4 induces ferroptosis by de- HER2 targeted therapy is used for HER2-positive breast grading ferritin and increasing cellular labile