Abstract
Ferroptosis, which is characterized by intracellular iron accumulation and lipid peroxidation, is a newly described form of regulated cell death that may play a key role in tumour suppression. In the present study, we investigated the expression profiles and biological effects of fascin actin-bundling protein 1 (Fascin, gene name FSCN1) in breast cancer. In addition, bioinformatics analysis of the TCGA cancer database and gain- and loss-of-function studies showed that Fascin enhances sensitivity to erastin-induced ferroptosis. Mechanistically, Fascin directly interacts with cysteine/glutamate transporter (xCT, gene name SLC7A11) and decreases its stability via the ubiquitin-mediated proteasome degradation pathway. Furthermore, we observed that Fascin is substantially upregulated in tamoxifen-resistant breast cancer cell lines, and drug-resistant cells were also more vulnerable to erastin-induced ferroptosis. Taken together, our findings reveal a previously unidentified role of Fascin in ferroptosis by regulating xCT. Thus, ferroptosis activation in breast cancer with high Fascin level may serve as a potential treatment.
Highlights
Breast cancer is the leading cause of cancer morbidity and mortality in women around the world [1]
Fascin is highly expressed in triple-negative breast cancer (TNBC) and enhances cells metastasis To gain initial insights into Fascin expression patterns in human breast cancer, we screened The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases
Immunohistochemistry staining For IHC staining, tissue slides were deparaffinized in xylene and rehydrated in alcohol, after which endogenous peroxidase was deactivated by cancer cell lines, including luminal, human epidermal growth factor receptor-2 (HER2)-positive, and TNBC types
Summary
Breast cancer is the leading cause of cancer morbidity and mortality in women around the world [1]. The biological behaviour, treatment, and prognosis of different breast cancer subtypes are significantly different [2]. Identifying effective therapeutic strategies and targets for different subtypes of breast cancer is a major focus of clinical research, especially for TNBC. Recent studies have confirmed that some types of tumour cells can be killed by inducing ferroptosis, including hepatocellular carcinoma [5], lung cancer [6], and gastric cancer [7]. Cancer cells that are resistant to conventional treatments or have a mesenchymal trait may be more vulnerable to ferroptosis [8], indicating a specific and novel therapeutic strategy for cancer research. As xCT is the primary functional subunit of system xc(−), elucidating the underlying mechanisms of xCT regulation in ferroptosis has been a focus of current research. The Fascin in specific subtypes of breast cancer as well as its function in cancer metastasis. Cells were seeded in a 12-well plate 1 day before treatment
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