scholarly journals YAP, CTGF, and Cyr61 are overexpressed in tamoxifen-resistant breast cancer and induce transcriptional repression of ERα

2021 ◽  
Author(s):  
Hyungjoo Kim ◽  
Seogho Son ◽  
Yunhyo Ko ◽  
Jeong Eon Lee ◽  
Sangmin Kim ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Transcriptional Repression ◽  
Estrogen Receptor Alpha ◽  
Tamoxifen Resistance ◽  
Tissue Growth ◽  
Tamoxifen Treatment ◽  
Transcriptional Level ◽  
Er Positive ◽  
Tamoxifen Resistant ◽  
Positive Breast Cancer

About 70% of breast cancer overexpresses estrogen receptor alpha (ERα). Tamoxifen, a competitive inhibitor of estrogen that binds to ER, has been widely used as a treatment for ER-positive breast cancer. However, 20-30% of breast cancer is resistant to tamoxifen treatment. The mechanisms underlying tamoxifen resistance remains elusive. We found that Yes-associated protein (YAP), connective tissue growth factor (CTGF), and cysteine-rich angiogenic inducer 61 (Cyr61) are overexpressed, while ERα is downregulated in tamoxifen-resistant breast cancer. Inhibition of YAP, CTGF, and Cyr61 restored ERα and increased sensitivity to tamoxifen. Overexpression of YAP, CTGF, and Cyr61 led to downregulation of ERα and conferred resistance to tamoxifen in ER-positive breast cancer cells. Mechanistically, CTGF and Cyr61 downregulated ERα expression at the transcriptional level by directly binding to the regulatory regions of ERα, leading to increased tamoxifen resistance. Also, CTGF induced Glut3 expression, leading to increased glycolysis, which enhanced cell proliferation and migration in tamoxifen-resistant cells. Together, these results demonstrate a novel role of YAP, CTGF, and Cyr61 in tamoxifen resistance and provide a molecular basis for their function in tamoxifen-resistant breast cancer.

scholarly journals NR4A1 Regulates Tamoxifen Resistance by Suppressing ERK Signaling in ER-Positive Breast Cancer

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1633
Author(s):  
Yu Cheon Kim ◽  
Clara Yuri Kim ◽  
Ji Hoon Oh ◽  
Myoung Hee Kim
Keyword(s):  
Breast Cancer ◽  
Tamoxifen Resistance ◽  
Erk Signaling ◽  
Tamoxifen Treatment ◽  
Loss Of Function ◽  
Mcf7 Cells ◽  
Er Positive ◽  
Tamoxifen Resistant ◽  
Positive Breast Cancer

Endocrine therapy is used to treat estrogen receptor (ER)-positive breast cancer. Tamoxifen is effective against this cancer subtype. Nonetheless, approximately 30% of patients treated with tamoxifen acquire resistance, resulting in therapeutic challenges. NR4A1 plays key roles in processes associated with carcinogenesis, apoptosis, DNA repair, proliferation, and inflammation. However, the role of NR4A1 in tamoxifen-resistant ER-positive breast cancer has not yet been elucidated. Here, we propose that NR4A1 is a promising target to overcome tamoxifen resistance. NR4A1 gene expression was downregulated in tamoxifen-resistant MCF7 (TamR) cells compared to that in MCF7 cells. Kaplan-Meier plots were used to identify high NR4A1 expression correlated with increased survival rates in patients with ER-positive breast cancer following tamoxifen treatment. Gain and loss of function experiments showed that NR4A1 restores sensitivity to tamoxifen by regulating cell proliferation, migration, invasion, and apoptosis. NR4A1 localized to the cytoplasm enhanced the expression of apoptotic factors. In silico and in vitro analyses revealed that NR4A1 enhanced responsiveness to tamoxifen by suppressing ERK signaling in ER-positive breast cancer, suggesting that the NR4A1/ERK signaling axis modulates tamoxifen resistance. These results indicate that NR4A1 could be a potential therapeutic target to overcome tamoxifen resistance in ER-positive breast cancer.

scholarly journals The Utility of SOX2 and AGR2 Biomarkers as Early Predictors of Tamoxifen Resistance in ER-Positive Breast Cancer Patients

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Yomna Zamzam ◽  
Yosra Abdelmonem Zamzam ◽  
Marwa Aboalsoud ◽  
Heba Harras
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Tamoxifen Resistance ◽  
Tamoxifen Treatment ◽  
Time To Failure ◽  
Breast Cancer Patients ◽  
Early Predictors ◽  
Er Positive ◽  
Group 1 ◽  
Positive Breast Cancer

Background. Despite the undeniable benefit of tamoxifen therapy for ER-positive breast cancer patients, approximately one-third of those patients either do not respond to tamoxifen or develop resistance. Thus, it is a crucial step to identify novel, reliable, and easily detectable biomarkers indicating resistance to this drug. Objective. The aim of this work is to explore SOX2 and AGR2 biomarker expression in the tumor tissue of ER-positive breast cancer patients in combination with the evaluation of serum AGR2 level of these patients in order to validate these biomarkers as early predictors of tamoxifen resistance. Methods. This study was conducted on 224 ER-positive breast cancer patients. All patients were primarily subjected to serum AGR2 levelling by ELISA and their breast cancer tissue immunostained for SOX2 and AGR2. After 5 years of follow-up, the patients were divided into 3 groups: group 1 was tamoxifen sensitive and groups 2 and 3 were tamoxifen resistant. Time to failure of tamoxifen treatment was considered the time from the beginning of tamoxifen therapy to the time of discovery of breast cancer recurrence or metastases (in months). Results. SOX2 and AGR2 biomarkers expression and serum AGR2 level were significantly higher in groups 2 and 3 in comparison to group 1, while the relationship between Her2 neu expression and Ki67 index in the 3 different groups was statistically nonsignificant. Lower SOX2 and AGR2 expression and low AGR2 serum levels in the studied patients of groups 2 and 3 were significantly associated with longer time-to-failure of tamoxifen treatment. According to the ROC curve, the combined use of studied markers validity was with a sensitivity of 100%, specificity of 96%, PPV 96%, and NPV 100% ( p < 0.001 ; AUC: 0.984). Conclusions. Integrated use of SOX2 and AGR2 biomarkers with serum AGR2 assay holds a promising hope for their future use as predictive markers for early detection of tamoxifen resistance in ER-positive breast cancer patients.

scholarly journals Association of tamoxifen resistance and lipid reprogramming in breast cancer

2018 ◽  
Author(s):  
Susanne Hultsch ◽  
Matti Kankainen ◽  
Lassi Paavolainen ◽  
Ruusu-Maaria Kovanen ◽  
Elina Ikonen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Cell Lines ◽  
Expression Patterns ◽  
Tamoxifen Resistance ◽  
Tamoxifen Treatment ◽  
Common Mechanism ◽  
Gene Expression Patterns ◽  
Er Positive ◽  
Tamoxifen Resistant

AbstractBackgroundTamoxifen treatment of estrogen receptor (ER)-positive breast cancer reduces mortality by 31%. However, over half of advanced ER-positive breast cancers are intrinsically resistant to tamoxifen and about 40% will acquire the resistance during the treatment.MethodsIn order to explore mechanisms underlying endocrine therapy resistance in breast cancer and to identify new therapeutic opportunities, we created tamoxifen-resistant breast cancer cell lines that represent the luminal A or the luminal B. Gene expression patterns revealed by RNA-sequencing in seven tamoxifen-resistant variants were compared with their isogenic parental cells. We further examined those transcriptomic alterations in a publicly available patient cohort.ResultsWe show that tamoxifen resistance cannot simply be explained by altered expression of individual genes, common mechanism across all resistant variants, or the appearance of new fusion genes. Instead, the resistant cell lines shared altered gene expression patterns associated with cell cycle, protein modification and metabolism, especially with the cholesterol pathway. In the tamoxifen-resistant T-47D cell variants we observed a striking increase of neutral lipids in lipid droplets as well as an accumulation of free cholesterol in the lysosomes. Tamoxifen-resistant cells were also less prone to lysosomal membrane permeabilization (LMP) and not vulnerable to compounds targeting the lipid metabolism. However, the cells were sensitive to disulfiram, LCS-1, and dasatinib.ConclusionAltogether, our findings highlight a major role of LMP prevention in tamoxifen resistance, and suggest novel drug vulnerabilities associated with this phenotype.

scholarly journals miR-449a Suppresses Tamoxifen Resistance in Human Breast Cancer Cells by Targeting ADAM22

2018 ◽  
Vol 50 (1) ◽  
pp. 136-149 ◽  
Author(s):  
Jun Li ◽  
Mingjie Lu ◽  
Jiao Jin ◽  
Xiyi Lu ◽  
Tongpeng Xu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Tamoxifen Resistance ◽  
Luciferase Assay ◽  
Protein Protein Interaction ◽  
Er Positive ◽  
Tamoxifen Resistant ◽  
Mcf 7 ◽  
Positive Breast Cancer

Background/Aims: Most of estrogen receptor positive breast cancer patients respond well initially to endocrine therapies, but often develop resistance during treatment with selective estrogen receptor modulators (SERMs) such as tamoxifen. Altered expression and functions of microRNAs (miRNAs) have been reportedly associated with tamoxifen resistance. Thus, it is necessary to further elucidate the function and mechanism of miRNAs in tamoxifen resistance. Methods: Tamoxifen sensitivity was validated by using Cell Counting Kit-8 in tamoxifen-sensitive breast cancer cells (MCF-7, T47D) and tamoxifen-resistant cells (MCF-7/TAM, T47D/ TAM). Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to detect the expression level of miR-449a in tamoxifen-sensitive/-resistant cells and patient serums. Dual-luciferase assay was used to identify the binding of miR-449a and predicted gene ADAM22. The expression level of ADAM22 was determined by qRT-PCR and western blotting in miR-449a +/- breast cancer cells. Subsequently, rescue experiments were carried out to identify the function of ADAM22 in miR-449a-reduced tamoxifen resistance. Finally, Gene ontology (GO) and Protein-protein interaction analyses were performed to evaluate the potential mechanisms of ADAM22 in regulating tamoxifen resistance. Results: MiR-449a levels were downregulated significantly in tamoxifen-resistant breast cancer cells when compared with their parental cells, as well as in clinical breast cancer serum samples. Overexpression of miR-449a re-sensitized the tamoxifen-resistant breast cancer cells, while inhibition of miR-449a conferred tamoxifen resistance in parental cells. Luciferase assay identified ADAM22 as a direct target gene of miR-449a. Additionally, silencing of ADAM22 could reverse tamoxifen resistance induced by miR-449a inhibition in ER-positive breast cancer cells. GO analysis results showed ADAM22 was mainly enriched in the biological processes of cell adhesion, cell differentiation, gliogenesis and so on. Protein-protein interaction analyses appeared that ADAM22 might regulate tamoxifen resistance through PPARG, LGI1, KRAS and LYN. Conclusion: Decreased miR-449a causes the upregulation of ADAM22, which induces tamoxifen resistance of breast cancer cells. These results suggest that miR-449a, functioning by targeting ADAM22, contributes to the mechanisms underlying breast cancer endocrine resistance, which may provide a potential therapeutic strategy in ER-positive breast cancers.

scholarly journals Network-based Approach to Identify Prognosis-related Genes in Tamoxifen-treated Patients With Estrogen Receptor-positive Breast Cancer

2020 ◽  
Author(s):  
Yanyan Wang ◽  
Xiaonan Gong ◽  
Yujie Zhang
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Protein Targeting ◽  
Quantitative Polymerase Chain Reaction ◽  
Tamoxifen Resistance ◽  
The Cancer Genome Atlas ◽  
Tamoxifen Treatment ◽  
Hub Genes ◽  
Er Positive ◽  
Positive Breast Cancer

Abstract Background: The estrogen receptor (ER) antagonist tamoxifen is the most commonly used endocrine therapy for ER-positive breast cancer. However, tamoxifen resistance remains a major cause of cancer recurrence and progression. Here, we aimed to identify hub genes involved in the progression and prognosis of ER-positive breast cancer following tamoxifen treatment.Results: Microarray data (GSE9838) for 155 tamoxifen-treated primary ER-positive breast cancer samples were obtained from the Gene Expression Omnibus database. In total, 1706 differentially expressed genes (DEGs) associated with tamoxifen resistance, including 859 upregulated genes and 847 downregulated genes, were identified. These DEGs were mainly enriched in functions such as protein targeting to the ER and pathways such as ribosome and oxidative phosphorylation.Weighted correlation network analysis (WGCNA) clustered genes into 13 modules, among which the tan and blue modules were the most significantly related to prognosis. From these two modules, we further identified three prognosis-related hub genes (GRSF1, MAPT, and REC8) via survival analysis. High expression ofGRSF1 predicted poor prognosis, whereas MAPT andREC8indicated favorable survival outcomes in all patients with breast cancer and in patients with ER-positive breast cancer based on The Cancer Genome Atlas database. These hub genes were further verified by reverse transcription quantitative polymerase chain reaction.Conclusion: Our findings established novel prognostic biomarkers to predict tamoxifen sensitivity, which may facilitate individualized management of breast cancer.

MLL3 Induced by Luteolin Causes Apoptosis in Tamoxifen-Resistant Breast Cancer Cells through H3K4 Monomethylation and Suppression of the PI3K/AKT/mTOR Pathway

2020 ◽  
Vol 48 (05) ◽  
pp. 1221-1241 ◽  
Author(s):  
Han-Tsang Wu ◽  
Yi-En Liu ◽  
Kai-Wen Hsu ◽  
Yu-Fen Wang ◽  
Ya-Chi Chan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Tamoxifen Resistance ◽  
Mtor Inhibitors ◽  
Ras Gene ◽  
Ras Genes ◽  
Er Positive ◽  
Tamoxifen Resistant ◽  
Positive Breast Cancer

Tamoxifen is one of the most common hormone therapy drug for estrogen receptor (ER)-positive breast cancer. Tumor cells with drug resistance often cause recurrence and metastasis in cancer patients. Luteolin is a natural compound found from various types of vegetables and exhibit anticancer activity in different cancers. This study demonstrated that luteolin inhibits the proliferation and induces apoptosis of tamoxifen-resistant ER-positive breast cancer cells. Luteolin also causes cell cycle arrest at the G2/M phase and decreases mitochondrial membrane potential. Besides, luteolin reduces the levels of activated PI3K/AKT/mTOR signaling pathway. The combination treatment of luteolin and PI3K, AKT, or mTOR inhibitors synergistically increases apoptosis in tamoxifen-resistant ER-positive breast cancer cells. Ras gene family (K-Ras, H-Ras, and N-Ras), an activator of PI3K, was transcriptionally repressed by luteolin via induction of tumor suppressor mixed-lineage leukemia 3 (MLL3) expression. MLL3 increases the level of monomethylation of Histone 3 Lysine 4 on the enhancer and promoter region of Ras genes, thus causes repression of Ras expressions. Our finding implies that luteolin was a promising natural agent against tamoxifen resistance of breast cancer.

scholarly journals Clinical CYP2D6 Genotyping to Personalize Adjuvant Tamoxifen Treatment in ER-Positive Breast Cancer Patients: Current Status of a Controversy

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 771
Author(s):  
Tessa A. M. Mulder ◽  
Mirjam de With ◽  
Marzia del Re ◽  
Romano Danesi ◽  
Ron H. J. Mathijssen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Outcome ◽  
Cancer Patients ◽  
Plasma Concentrations ◽  
Tamoxifen Treatment ◽  
Current Status ◽  
Endocrine Treatment ◽  
Breast Cancer Patients ◽  
Er Positive ◽  
Positive Breast Cancer

Tamoxifen is a major option for adjuvant endocrine treatment in estrogen receptor (ER) positive breast cancer patients. The conversion of the prodrug tamoxifen into the most active metabolite endoxifen is mainly catalyzed by the enzyme cytochrome P450 2D6 (CYP2D6). Genetic variation in the CYP2D6 gene leads to altered enzyme activity, which influences endoxifen formation and thereby potentially therapy outcome. The association between genetically compromised CYP2D6 activity and low endoxifen plasma concentrations is generally accepted, and it was shown that tamoxifen dose increments in compromised patients resulted in higher endoxifen concentrations. However, the correlation between CYP2D6 genotype and clinical outcome is still under debate. This has led to genotype-based tamoxifen dosing recommendations by the Clinical Pharmacogenetic Implementation Consortium (CPIC) in 2018, whereas in 2019, the European Society of Medical Oncology (ESMO) discouraged the use of CYP2D6 genotyping in clinical practice for tamoxifen therapy. This paper describes the latest developments on CYP2D6 genotyping in relation to endoxifen plasma concentrations and tamoxifen-related clinical outcome. Therefore, we focused on Pharmacogenetic publications from 2018 (CPIC publication) to 2021 in order to shed a light on the current status of this debate.

scholarly journals Poly-ADP-Ribosylation of Estrogen Receptor-Alpha by PARP1 Mediates Antiestrogen Resistance in Human Breast Cancer Cells

Cancers ◽  
2019 ◽  
Vol 11 (1) ◽  
pp. 43 ◽  
Author(s):  
Nicholas Pulliam ◽  
Jessica Tang ◽  
Weini Wang ◽  
Fang Fang ◽  
Riddhi Sood ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Oxidative Stress ◽  
Estrogen Receptor ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Target Genes ◽  
Tamoxifen Resistance ◽  
Tamoxifen Treatment ◽  
Dependent Manner ◽  
Tamoxifen Resistant

Therapeutic targeting of estrogen receptor-α (ERα) by the anti-estrogen tamoxifen is standard of care for premenopausal breast cancer patients and remains a key component of treatment strategies for postmenopausal patients. While tamoxifen significantly increases overall survival, tamoxifen resistance remains a major limitation despite continued expression of ERα in resistant tumors. Previous reports have described increased oxidative stress in tamoxifen resistant versus sensitive breast cancer and a role for PARP1 in mediating oxidative damage repair. We hypothesized that PARP1 activity mediated tamoxifen resistance in ERα-positive breast cancer and that combining the antiestrogen tamoxifen with a PARP1 inhibitor (PARPi) would sensitize tamoxifen resistant cells to tamoxifen therapy. In tamoxifen-resistant vs. -sensitive breast cancer cells, oxidative stress and PARP1 overexpression were increased. Furthermore, differential PARylation of ERα was observed in tamoxifen-resistant versus -sensitive cells, and ERα PARylation was increased by tamoxifen treatment. Loss of ERα PARylation following treatment with a PARP inhibitor (talazoparib) augmented tamoxifen sensitivity and decreased localization of both ERα and PARP1 to ERα-target genes. Co-administration of talazoparib plus tamoxifen increased DNA damage accumulation and decreased cell survival in a dose-dependent manner. The ability of PARPi to overcome tamoxifen resistance was dependent on ERα, as lack of ERα-mediated estrogen signaling expression and showed no response to tamoxifen-PARPi treatment. These results correlate ERα PARylation with tamoxifen resistance and indicate a novel mechanism-based approach to overcome tamoxifen resistance in ER+ breast cancer.

scholarly journals Dynamic surveillance of tamoxifen‐resistance in ER‐positive breast cancer by CAIX‐targeted ultrasound imaging

2020 ◽  
Vol 9 (7) ◽  
pp. 2414-2426
Author(s):  
Ying Li ◽  
Xiaoyu Chen ◽  
ZhiWei Zhou ◽  
Qing Li ◽  
Kenneth D. Westover ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Ultrasound Imaging ◽  
Tamoxifen Resistance ◽  
Targeted Ultrasound ◽  
Er Positive ◽  
Positive Breast Cancer
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