scholarly journals Genomic interaction between ER and HMGB2 identifies DDX18 as a novel driver of endocrine resistance in breast cancer cells

Oncogene ◽  
2014 ◽  
Vol 34 (29) ◽  
pp. 3871-3880 ◽  
Author(s):  
A M Redmond ◽  
C Byrne ◽  
F T Bane ◽  
G D Brown ◽  
P Tibbitts ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Endocrine Resistance ◽  
Genomic Interaction

scholarly journals Fatty Acid Synthase Confers Tamoxifen Resistance to ER+/HER2+ Breast Cancer

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1132
Author(s):  
Javier A. Menendez ◽  
Adriana Papadimitropoulou ◽  
Travis Vander Steen ◽  
Elisabet Cuyàs ◽  
Bharvi P. Oza-Gajera ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Fatty Acid ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Promoter Activity ◽  
Fatty Acid Synthase ◽  
Endocrine Resistance ◽  
Gene Promoter ◽  
Her2 Positive ◽  
Her2 Breast Cancer

The identification of clinically important molecular mechanisms driving endocrine resistance is a priority in estrogen receptor-positive (ER+) breast cancer. Although both genomic and non-genomic cross-talk between the ER and growth factor receptors such as human epidermal growth factor receptor 2 (HER2) has frequently been associated with both experimental and clinical endocrine therapy resistance, combined targeting of ER and HER2 has failed to improve overall survival in endocrine non-responsive disease. Herein, we questioned the role of fatty acid synthase (FASN), a lipogenic enzyme linked to HER2-driven breast cancer aggressiveness, in the development and maintenance of hormone-independent growth and resistance to anti-estrogens in ER/HER2-positive (ER+/HER2+) breast cancer. The stimulatory effects of estradiol on FASN gene promoter activity and protein expression were blunted by anti-estrogens in endocrine-responsive breast cancer cells. Conversely, an AKT/MAPK-related constitutive hyperactivation of FASN gene promoter activity was unaltered in response to estradiol in non-endocrine responsive ER+/HER2+ breast cancer cells, and could be further enhanced by tamoxifen. Pharmacological blockade with structurally and mechanistically unrelated FASN inhibitors fully impeded the strong stimulatory activity of tamoxifen on the soft-agar colony forming capacity—an in vitro metric of tumorigenicity—of ER+/HER2+ breast cancer cells. In vivo treatment with a FASN inhibitor completely prevented the agonistic tumor-promoting activity of tamoxifen and fully restored its estrogen antagonist properties against ER/HER2-positive xenograft tumors in mice. Functional cancer proteomic data from The Cancer Proteome Atlas (TCPA) revealed that the ER+/HER2+ subtype was the highest FASN protein expressor compared to basal-like, HER2-enriched, and ER+/HER2-negative breast cancer groups. FASN is a biological determinant of HER2-driven endocrine resistance in ER+ breast cancer. Next-generation, clinical-grade FASN inhibitors may be therapeutically relevant to countering resistance to tamoxifen in FASN-overexpressing ER+/HER2+ breast carcinomas.

scholarly journals Transcriptional coregualtor NUPR1 maintains tamoxifen resistance in breast cancer cells

2021 ◽  
Vol 12 (2) ◽  
Author(s):  
Lingling Wang ◽  
Jiashen Sun ◽  
Yueyuan Yin ◽  
Yanan Sun ◽  
Jinyi Ma ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Critical Role ◽  
Endocrine Resistance ◽  
Autophagic Flux ◽  
Physical Interaction ◽  
Premature Senescence ◽  
Breast Cancers ◽  
Transcriptional Coregulator

AbstractTo support cellular homeostasis and mitigate chemotherapeutic stress, cancer cells must gain a series of adaptive intracellular processes. Here we identify that NUPR1, a tamoxifen (Tam)-induced transcriptional coregulator, is necessary for the maintenance of Tam resistance through physical interaction with ESR1 in breast cancers. Mechanistically, NUPR1 binds to the promoter regions of several genes involved in autophagy process and drug resistance such as BECN1, GREB1, RAB31, PGR, CYP1B1, and regulates their transcription. In Tam-resistant ESR1 breast cancer cells, NUPR1 depletion results in premature senescence in vitro and tumor suppression in vivo. Moreover, enforced-autophagic flux augments cytoplasmic vacuolization in NUPR1-depleted Tam resistant cells, which facilitates the transition from autophagic survival to premature senescence. Collectively, these findings suggest a critical role for NUPR1 as a transcriptional coregulator in enabling endocrine persistence of breast cancers, thus providing a vulnerable diagnostic and/or therapeutic target for endocrine resistance.

scholarly journals Structural and Molecular Mechanisms of Cytokine-Mediated Endocrine Resistance in Human Breast Cancer Cells

2017 ◽  
Vol 65 (6) ◽  
pp. 1122-1135.e5 ◽  
Author(s):  
Joshua D. Stender ◽  
Jerome C. Nwachukwu ◽  
Irida Kastrati ◽  
Yohan Kim ◽  
Tobias Strid ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Human Breast Cancer ◽  
Breast Cancer Cells ◽  
Molecular Mechanisms ◽  
Endocrine Resistance ◽  
Human Breast Cancer Cells ◽  
Human Breast

scholarly journals ZNF213 facilitates ER alpha signaling in breast cancer cells

2020 ◽  
Author(s):  
Ting Zhuang ◽  
Huijie Yang ◽  
Wuchen Zhao ◽  
Xin Li ◽  
Zhiguo Niu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Protein Stability ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Zinc Finger Protein ◽  
Endocrine Resistance ◽  
Luciferase Assay ◽  
Clinical Issue ◽  
Er Alpha ◽  
Positive Breast Cancer

Abstract Background Breast cancer is the most common women malignancy worldwide, while estrogen receptor alpha positive type accounts for two third of all breast cancers. Although ER alpha positive breast cancer could be effectively controlled by endocrine therapy, more than half of the cases could develop endocrine resistance, making it an important clinical issue in breast cancer treatment. Thus, decoding the detailed mechanism, which controls ER alpha signaling activation and ER alpha protein stability, is of great importance for the improvement of breast cancer therapy. Methods ZNF213 and ER alpha protein expression level were measured by western blot, while ER alpha target genes were determined by QPCR. WST-1 assay was used to measure cell proliferation. RNA sequence was performed by Ingenuity pathway analysis. The ER alpha signaling activities were measured with luciferase assay, QPCR and western blotting. Protein stability assay and ubiquitin assay were used to determine ER alpha protein degradation and ubiquitination. The immuno-precipation was utilized to determine ER alpha and ZNF213 interaction. The ubiquitin-based immuno-precipitation assay was sued to detect specific ubiquitination manner on ER alpha. The prognostic data of ZNF213 was derived from public available database. Results Here, we identified ZNF213 as a novel zinc finger protein, which modulates ER alpha protein. ZNF213 expression correlates with poor outcome in endocrine treated patients. ZNF213 depletion inhibits ER alpha signaling and proliferation in breast cancer cells. Further mechanistic studies show that ZNF213 is located in cytosol and nuclear, which modulates ER alpha stability via inhibiting ER alpha K48-linked ubiquitination. Conclusions Our study reveals an interesting post-translational mechanism between ER alpha and ZNF213 in breast cancer. Targeting ZNF213 could be an appealing strategy for ER alpha positive breast cancer.

scholarly journals Cyclin E2 Overexpression Is Associated with Endocrine Resistance but not Insensitivity to CDK2 Inhibition in Human Breast Cancer Cells

2012 ◽  
Vol 11 (7) ◽  
pp. 1488-1499 ◽  
Author(s):  
C. Elizabeth Caldon ◽  
C. Marcelo Sergio ◽  
Jian Kang ◽  
Anita Muthukaruppan ◽  
Marijke N. Boersma ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Human Breast Cancer ◽  
Breast Cancer Cells ◽  
Endocrine Resistance ◽  
Human Breast Cancer Cells ◽  
Human Breast ◽  
Cyclin E2

HNRNPA2B1 regulates tamoxifen- and fulvestrant-sensitivity and hallmarks of endocrine resistance in breast cancer cells

2021 ◽  
Author(s):  
Belinda J. Petri ◽  
Kellianne M. Piell ◽  
Gordon C. South Whitt ◽  
Ali E. Wilt ◽  
Claire C. Poulton ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Endocrine Resistance

scholarly journals Epitranscriptomic Reader HNRNPA2B1 Confers Endocrine Resistance to Breast Cancer Cells

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A807-A808
Author(s):  
Carolyn M Klinge ◽  
Belinda J Petri ◽  
Kellianne M Piell
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Growth Inhibition ◽  
Cancer Cells ◽  
Metastatic Disease ◽  
Colony Size ◽  
Breast Cancer Cells ◽  
Endocrine Resistance ◽  
Soft Agar ◽  
Mcf 7

Abstract Despite new combination therapies improving survival of breast cancer patients with estrogen receptor α (ER+) tumors, the molecular mechanisms for endocrine-resistant metastatic disease remain unresolved. HNRNPA2B1 (Heterogeneous Nuclear Ribonucleoprotein A2/B1), an RNA binding protein that functions as reader of the N(6)-methyladenosine (m6A) mark in transcribed RNA, is upregualted in tamoxifen- and fulvestrant-resistant, estrogen receptor (ERα)+ LCC9 and LY2 cells derived from MCF-7 endocrine-sensitive luminal A breast cancer cells (1). The miRNA-seq transcriptome of MCF-7 cells transiently overexpressing HNRNPA2B1 (A2B1) identified gene ontology (GO) pathways including “cellular response to steroid hormone signaling and estradiol” and “positive regulation of protein ser/thr kinase activity”. Modest (~ 4.5-fold) stable HNRNPA2B1 overexpression in MCF-7 cells (MCF-7-A2B1) results in ablation of growth inhibition by 4-hydroxytamoxifen (4-OHT) and fulvestrant. This was not due to loss or decrease of ERα; in fact, ERα was increased. Conversely, transient knockdown of HNRNPA2B1 in LCC9 and LY2 cells sensitized the cells to growth inhibition by 4-OHT and fulvestrant while reducing ERα. MCF-7-A2B1 cells showed increased migration, invasion, clonogenicity, soft agar colony size, and markers of epithelial-to-mesenchymal transition. Like LCC9 cells, MCF-7-A2B1 cells showed activation of AKT and MAPK and high androgen receptor (AR). Treatment of MCF-7-A2B1 cells with either PI3K inhibitor Wortmannin or MEK inhibitor PD98059 inhibited soft agar colony formation and reduced colony size. Knockdown of HNRNPA2B1 in MCF-7-A2B1 reduces clonogenicity, but had no effect on the clonogenicity of either LCC9 or LY2 cells. These data suggest a role for HNRNPA2B1 in promoting the initiation of acquired endocrine-resistance by activating ser/thr kinase growth factor signaling pathways. Selective inhibition of HNRNPA2B1 may be a target to prevent acquistion of endocrine therapy resistance, but not treat established metastatic disease. Reference: (1) Klinge CM, Piell KM, Tooley CS, Rouchka EC. HNRNPA2/B1 is upregulated in endocrine-resistant LCC9 breast cancer cells and alters the miRNA transcriptome when overexpressed in MCF-7 cells. Scientific reports 2019; 9:9430

scholarly journals Amphiregulin retains ERα expression in acquired aromatase inhibitor resistant breast cancer cells

2020 ◽  
Vol 27 (12) ◽  
pp. 671-683
Author(s):  
Yuanzhong Wang ◽  
Yen-Dun Tony Tzeng ◽  
Gregory Chang ◽  
Xiaoqiang Wang ◽  
Shiuan Chen
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Egf Receptor ◽  
Acquired Resistance ◽  
Endocrine Resistance ◽  
Ectopic Expression ◽  
Clinical Issue ◽  
Forkhead Box M1 ◽  
Estrogen Production

Acquired resistance to aromatase inhibitors (AIs) is a significant clinical issue in endocrine therapy for estrogen receptor (ER) positive breast cancer which accounts for the majority of breast cancer. Despite estrogen production being suppressed, ERα signaling remains active and plays a key role in most AI-resistant breast tumors. Here, we found that amphiregulin (AREG), an ERα transcriptional target and EGF receptor (EGFR) ligand, is crucial for maintaining ERα expression and signaling in acquired AI-resistant breast cancer cells. AREG was deregulated and critical for cell viability in ER+ AI-resistant breast cancer cells, and ectopic expression of AREG in hormone responsive breast cancer cells promoted endocrine resistance. RNA-sequencing and reverse phase protein array analyses revealed that AREG maintains ERα expression and signaling by activation of PI3K/Akt/mTOR signaling and upregulation of forkhead box M1 (FOXM1) and serum- and glucocorticoid-inducible kinase 3 (SGK3) expression. Our study uncovers a previously unappreciated role of AREG in maintaining ERα expression and signaling, and establishes the AREG-ERα crosstalk as a driver of acquired AI resistance in breast cancer.

scholarly journals Comprehensive Transcriptomic Analysis Reveals Dysregulated Competing Endogenous RNA Network in Endocrine Resistant Breast Cancer Cells

2020 ◽  
Vol 10 ◽  
Author(s):  
Liang Gao ◽  
Kunwei Shen ◽  
Ni Yin ◽  
Min Jiang
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Endocrine Therapy ◽  
Breast Cancer Cells ◽  
Regulatory Networks ◽  
Endocrine Resistance ◽  
Differentially Expressed ◽  
Circular Rnas ◽  
Competing Endogenous Rna ◽  
Non Coding Rnas

BackgroundTamoxifen and fulvestrant, both approved for endocrine therapy, have remarkably increased the prognosis of hormone receptor-positive breast cancer patients. However, acquired resistance to endocrine therapy greatly reduces its clinical efficacy. Accumulating evidence suggests a pivotal role of non-coding RNAs (ncRNAs) in breast cancer endocrine resistance, but the specific functions of ncRNAs in tamoxifen and fulvestrant resistance remain largely unknown.MethodsMicroarray analysis was performed for endocrine therapy sensitive (MCF-7), tamoxifen-resistant (LCC2), and dual tamoxifen and fulvestrant-resistant (LCC9) breast cancer cells. Gene ontology and pathway analysis were conducted for functional prediction of the unannotated differentially expressed ncRNAs. Competing endogenous RNA regulatory networks were constructed.ResultsWe discovered a total of 3,129 long non-coding RNAs (lncRNAs), 13,556 circular RNAs (circRNAs), 132 microRNAs, and 3358 mRNAs that were significantly differentially expressed. We constructed co-expression networks for lncRNA-mRNA, circRNA-mRNA, and microRNA-mRNA. In addition, we established lncRNA-microRNA-mRNA and circRNA-microRNA-mRNA regulatory networks to depict ncRNA crosstalk and transcriptomic regulation of endocrine resistance.ConclusionsOur study delineates a comprehensive profiling of ncRNAs in tamoxifen and fulvestrant resistant breast cancer cells, which enriches our understanding of endocrine resistance and sheds new light on identifying novel endocrine resistance biomarkers and potential therapeutic targets to overcome endocrine resistance.

Sign in / Sign up

Export Citation Format

Share Document