The aim of the present study was to clarify the activation of ferroptosis in different breast cancer cells by sulfasalazine (SAS) and to explore the relationship between the estrogen receptor (ER) and the transferrin receptor (TFRC). MDA-MB-231 and T47D cells were treated with SAS for 24 h. Changes in cell morphology were observed under a microscope. CCK-8 was used to detect the proliferation inhibition rate and determine the IC 50 values. Western blotting was used to detect the expression of glutathione peroxidase 4 (GPX4) and xCT. Flow cytometry was used to identify changes in the production of reactive oxygen species (ROS). Mitochondrial morphological changes in T47D were observed using transmission electron microscopy. Changes in the mitochondrial membrane potential (MMP) were observed using confocal fluorescence microscopy. RT-PCR was used to detect the mRNA expression levels of TFRC and divalent metal transporter 1 (DMT1). Bioinformatics analysis was performed on TFRC expression in 1,208 breast cancer samples and its relationship with ER. TFRC expression was detected in various breast cancer tissues using immunohistochemistry and in various breast cancer cells using western blotting. Small interfering RNA (siRNA) knocked down ER expression in T47D cells, and changes in the TFRC mRNA and protein levels were observed. RT-PCR was used to detect TFRC expression in 87 clinical specimens. The results of the present study revealed that SAS could inhibit breast cancer cell viability, which was accompanied by an abnormal increase in ROS and a depletion of GPX4 and system x c-. Liproxstatin-1 reversed the SAS-induced increase in ROS. The cells treated with SAS had shrunken mitochondria and decreased MMP. SAS upregulated TFRC and DMT1. Knockdown of the ER increased TFRC expression in breast cancer cells. Immunohistochemistry indicated that TFRC expression was lower in ER + tissues than in ERtissues. After confirmation with RT-PCR in 87 clinical specimens, TFRC expression in ERtissue was revealed to be significantly higher than that of ER + tissue. In conclusion SAS could trigger ferroptosis in breast cancer cells, especially in cells with low ER expression. Therefore, SAS is a potential agent for breast cancer treatment.
Chemokine (C-X-C motif) ligand 1 (CXCL1), a member of the CXC chemokine family, has been reported to be a critical factor in inflammatory diseases and tumor progression; however, its functions and molecular mechanisms in estrogen receptor α (ER)-negative breast cancer (BC) remain largely unknown. The present study demonstrated that CXCL1 was upregulated in ER-negative BC tissues and cell lines compared with ER-positive tissues and cell lines. Treatment with recombinant human CXCL1 protein promoted ER-negative BC cell migration and invasion in a dose-dependent manner, and stimulated the activation of phosphorylated (p)- extracellular signal-regulated kinase (ERK)1/2, but not p-STAT3 or p-AKT. Conversely, knockdown of CXCL1 in BC cells attenuated these effects. Additionally, CXCL1 increased the expression of matrix metalloproteinase (MMP)2/9 via the ERK1/2 pathway. Inhibition of MEK1/2 by its antagonist U0126 reversed the effects of CXCL1 on MMP2/9 expression. Furthermore, immunohistochemical analysis revealed a strong positive association between CXCL1 and p-ERK1/2 expression levels in BC tissues. In conclusion, the present study demonstrated that CXCL1 is highly expressed in ER-negative BC, and stimulates BC cell migration and invasion via the ERK/MMP2/9 pathway. Therefore, CXCL1 may serve as a potential therapeutic target in ER-negative BC.
Background: Triple-negative breast cancer (TNBC) was characterized by breast cancers that do not express estrogen receptor (ER), progesterone receptor (PR), or human epidermal growth factor receptor (HER)-2 genes. TNBC patients are associated with a shorter median time to relapse and death for the lack of available treatment targets. Long non-coding RNAs (LncRNAs) have been reported to play an important role in the development of TNBC. We identified a novel breast-specific long non-coding RNA LINC00993, but less was known about its expression pattern and functional role in TNBC. Methods: LINC00993 RNA expression was detected across different types of clinical breast cancer samples by using qRT-PCR. Bioinformatic methods "guilt by association" and gene set enrichment analysis (GSEA) were used to predict LINC00993 functions. Subcellular localization of LINC00993 in cells was detected by RNA fluorescence in situ hybridization (FISH). Effect of LINC00993 on cell growth was measured by plate colony formation assays, typical growth curve, and an in vivo tumor model. Cell cycle analysis was done by flow cytometry analysis. Key cell cycle regulators were detected by Western blot. Results: LINC00993 was largely downregulated in TNBC, and higher expression indicated better outcome. LINC00993 located mainly in the nucleus. LINC00993 suppressed TNBC growth both in vitro and in vivo. LINC00993 was predicted to be involved in cell cycle pathways by using "guilt by association" and GSEA methods. Key cell cycle regulators like p16 INK4A , p14 ARF , p53, and p21 were affected by LINC00993 overexpression. Conclusions: A new breast-specific lincRNA LINC00993 was identified with a tumorsuppressive feature and with prognostic value. This is the first research on LINC00993 function. Our results suggest that controlling LINC00993 level may be beneficial for breast cancer treatment.
Background: Pyroptosis is a new form of programmed cell death (PCD), also known as cellular inflammatory necrosis. Its discovery has resulted in a novel approach to the progression and medication resistance of breast cancer (BC). However, there is still a significant gap in the investigation of pyroptosis-related genes in BC. Methods: The mRNA expression profiles and clinical data of BC patients were obtained from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. Then, using the TCGA cohort, we created a predictive multigene signature including pyroptosis-related genes and verified it using the two GEO cohorts. A pyroptosis-related gene signature was created by combining several bioinformatics and statistical methodologies to predict patient prognosis and responses to immunotherapy and chemotherapy. Furthermore, a nomogram based on the gene signature and clinicopathological markers was created to better classify the risk and quantify the risk assessment of individual patients. Results: A pyroptosis-related gene signature consisting of 15 genes was established. The pyroptosis-related gene signature classified the patients into two groups: high-risk and low-risk. When combined with clinical variables, the risk score was discovered to be an independent predictor of overall survival (OS) in BC patients. Some immunological pathways and genes were linked to pyroptosis, according to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) evaluations. Patients in the high-risk group had a worse prognosis and were not very sensitive to immunotherapy. However, several chemotherapeutic agents were predicted to have greater potential for patients in the high-risk group. Finally, a nomogram was developed that included a classifier based on the 15 pyroptosis-related genes, tumor stage, age, and histologic grade. This nomogram demonstrated good classification capacity and might help with clinical decision-making in BC.
Purpose: Effective predictors of the response to neoadjuvant chemotherapy (NAC) are still insufficient. This study aimed to investigate the predictive value of serum lipid profiles for the response to NAC in breast cancer patients. Methods: A total of 533 breast cancer patients who had received NAC were retrospectively studied. The pretreatment of serum lipids, including total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and lipoprotein-α, and clinicopathological characteristics were collected to assess their predictive roles. Results: Breast cancer patients had significantly lower TC, TG, HDL-C, and LDL-C levels than normal individuals. Among these indicators, TG and LDL-C levels and HDL-C level increased and decreased significantly after NAC, respectively. In estrogen receptor (ER)positive patients, increased LDL-C level was associated with better outcomes. Moreover, the receiver operating characteristic curve analyses suggested that TG and HDL-C levels at diagnosis can be used as predictors of the response to NAC only in the ER-positive subgroup. According to univariate analyses, patients with low TG level (< 1.155 mmol/L) or high HDL-C level (≥ 1.305 mmol/L) in the ER-positive subgroup had more favorable clinical responses than the other patients in the subgroup. Furthermore, according to multivariate analyses, a high HDL-C level (≥ 1.305 mmol/L, p = 0.007) was an independent predictor of NAC efficacy. Conclusion: High HDL-C level (≥ 1.305 mmol/L) before NAC and increased LDL-C level after NAC were associated with the better treatment response in ER-positive breast cancer patients. These results are potentially considered beneficial in establishing treatment decisions.
Breast cancer is one of the most common malignancies and the leading cause of cancer-associated death among women. Anterior gradient 3 (AGR3) is a cancer-associated gene and is similar to its homologous oncogene AGR2. However, whether AGR3 participates in breast cancer progression remains unclear. The present study aimed to investigate the function of AGR3 in ER-positive breast cancer. In the present study, reverse transcription-quantitative PCR was used to detect AGR3 mRNA expression in breast cancer tissues and cell lines; linear correlation analysis was used to investigate the correlation between AGR3 and estrogen receptor 1 (ESR1) expression in breast cancer via GEO dataset analysis; western blotting was used to assess the levels of AGR3, ER and GAPDH; small interfering (si)RNA transfection was used to knock down AGR3 and ESR1 expression; and finally the Cell Counting Kit-8 assay was used to evaluate cell viability. In the present study, AGR3 expression was markedly increased in estrogen receptor (ER)-positive breast cancer tissues and cell lines compared with that in ER-negative breast cancer. AGR3 expression was upregulated in estrogen-treated T47D cells, whereas 4-hydroxytamoxifen, an inhibitor of estrogen-ER activity in breast cancer cells, downregulated AGR3 expression in T47D cells. Functional assays demonstrated that knockdown of AGR3 using siRNAs inhibited T47D cell proliferation compared with that of the negative control group. Additionally, AGR3 expression was decreased after knocking down ESR1. The present results suggested that AGR3 may serve an important role in estrogen-mediated cell proliferation in breast cancer and that AGR3 knockdown may be a potential therapeutic strategy for ER-positive breast cancer.
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