scholarly journals The Emerging Role of ESR1 Mutations in Luminal Breast Cancer as a Prognostic and Predictive Biomarker of Response to Endocrine Therapy

Cancers ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 1894 ◽  
Author(s):  
Irene De Santo ◽  
Amelia McCartney ◽  
Ilenia Migliaccio ◽  
Angelo Di Leo ◽  
Luca Malorni
Keyword(s):  
Breast Cancer ◽  
Endocrine Resistance ◽  
Metastatic Breast ◽  
Predictive Biomarker ◽  
Clinical Findings ◽  
Luminal Breast Cancer ◽  
Breast Cancers ◽  
Er Positive ◽  
Esr1 Mutations

Mutations in the hotspot ligand-binding domain of the estrogen receptor (ER) gene ESR1 have recently been recognized as mechanisms of endocrine resistance in endocrine receptor-positive metastatic breast cancer (MBC). Accumulating data suggest these mutations develop under the selective pressure of endocrine treatments, and are infrequent in untreated ER-positive breast cancers. In vitro studies show that these mutations confer ligand-independent activity, resistance to estrogen deprivation, and relative resistance to tamoxifen and fulvestrant. Post-hoc retrospective and prospective analyses of ESR1 mutations in patients with MBC have consistently found that these mutations are markers of poor prognosis and predict resistance to aromatase inhibitors (AIs). These results warrant further investigation and prospective validation in dedicated studies. Moreover, studies are ongoing to clarify the activity of novel drugs in the context of metastatic endocrine resistant luminal breast cancer harboring ESR1 mutations. In this review, we summarize the pre-clinical and clinical findings defining the characteristics of ESR1 mutant breast cancer, and highlight the potential clinical developments in this field.

scholarly journals Are We Ready to Use ESR1 Mutations in Clinical Practice

Breast Care ◽  
2017 ◽  
Vol 12 (5) ◽  
pp. 309-313 ◽  
Author(s):  
Rinath Jeselsohn
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Aromatase Inhibitors ◽  
Endocrine Resistance ◽  
Metastatic Breast ◽  
Circulating Tumor Dna ◽  
Breast Cancers ◽  
Poor Overall Survival ◽  
Treatment Naïve ◽  
Esr1 Mutations

The recurrent ligand-binding domain ESR1 mutations are an important mechanism of endocrine resistance in estrogen receptor-positive (ER+) metastatic breast cancer. These mutations evolve under the selective pressure of endocrine treatments and are rarely found in treatment-naïve ER+ breast cancers. Preclinical studies showed that these mutations lead to ligand-independent activity facilitating resistance to aromatase inhibitors and relative resistance to tamoxifen and fulvestrant. Retrospective analyses of ESR1 mutations in baseline plasma circulating tumor DNA from clinical trials suggest that these mutations are prognostic of poor overall survival and predictive of resistance to aromatase inhibitors in metastatic disease. Larger datasets and prospective studies to confirm these results are lacking. In addition, response to other standard treatments for metastatic breast cancer in the presence of the ESR1 mutations is unknown, and studies to determine the optimal treatment combinations for patients with ESR1 mutations are also needed.

Detection of estrogen receptor in bone marrow from patients with metastatic breast cancer.

1987 ◽  
Vol 5 (11) ◽  
pp. 1779-1782 ◽  
Author(s):  
U Berger ◽  
J L Mansi ◽  
P Wilson ◽  
R C Coombes
Keyword(s):  
Breast Cancer ◽  
Bone Marrow ◽  
Endocrine Therapy ◽  
Tumor Cells ◽  
Epithelial Membrane Antigen ◽  
Metastatic Breast ◽  
Breast Cancers ◽  
Double Staining ◽  
Primary Tumors ◽  
Er Positive

We devised a method of detecting estrogen receptors (ER) in bone marrow metastases from patients with breast cancer. The method involves a sequential double-staining immunocytochemical technique, with a monoclonal antibody to ER and a polyclonal antibody recognizing epithelial membrane antigen to confirm the epithelial nature of suspected tumor cells. Twenty-seven patients were assessed: ten were found to have ER-positive tumor cells in the bone marrow; ten had ER-negative cells; and the remaining seven patients had no tumor cells in the bone marrow smears. Of the ten patients with ER-positive cells, eight (80%) either had a response to endocrine therapy, implying that they possess ER-positive breast cancers, or had ER-positive primary tumors as determined by the dextran-coated charcoal biochemical assay (DCC). Of the ten patients with ER-negative cells in the bone marrow, eight failed to respond to endocrine therapy. This technique therefore provides a means of predicting which patients will respond to endocrine therapy, and is particularly important in those patients whose ER status is unknown.

scholarly journals Estrogen deprivation triggers an immunosuppressive phenotype in breast cancer cells

2019 ◽  
Author(s):  
Daniela Hühn ◽  
Pablo Martí-Rodrigo ◽  
Silvana Mouron ◽  
Catherine S. Hansel ◽  
Kirsten Tschapalda ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Breast Cancers ◽  
Breast Cancer Patients ◽  
Mcf7 Cells ◽  
Estrogen Deprivation ◽  
Er Positive

ABSTRACTEstrogen receptor (ER)-positive breast tumors are routinely treated with estrogen-depriving therapies. Despite their effectiveness, patients often progress into a more aggressive form of the disease. Through a chemical screen oriented to identify chemicals capable of inducing the expression of the immune-checkpoint ligand PD-L1, we found antiestrogens as hits. Subsequent validations confirmed that estrogen deprivation or ERα depletion induces PD-L1 expression in ER-positive breast cancer cells, both in vitro and in vivo. Likewise, PD-L1 expression is increased in metastasis arising from breast cancer patients receiving adjuvant hormonal therapy for their local disease. Transcriptome analyses indicate that estrogen deprivation triggers a broad immunosuppressive program, not restricted to PD-L1. Accordingly, estrogen deprived MCF7 cells are resistant to T-cell mediated cell killing, in a manner that can be reverted by estradiol. Our study reveals that while antiestrogen therapies effectively limit tumor growth in ER-positive breast cancers, they also trigger a transcriptional program that favors immune evasion.

scholarly journals Liquid Biopsy: New Tool to Overcome CDKi Resistance Mechanism in Luminal Metastatic Breast Cancer

2021 ◽  
Author(s):  
Miriam González-Conde ◽  
Celso Yanez ◽  
Rafael López-López ◽  
Clotilde Costa
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Cancer Patients ◽  
Liquid Biopsy ◽  
Hormone Receptors ◽  
Endocrine Resistance ◽  
Metastatic Breast ◽  
Luminal Breast Cancer ◽  
Breast Cancer Patients ◽  
Her2 Breast Cancer

Breast cancer is the most commonly diagnosed cancer in women worldwide. Approximately, 70 % of breast cancer patients express hormone receptors (HR) (Luminal subtype). Adjuvant endocrine treatments are the standard of care in HR+/HER2- breast cancer. Over time, about 50% of those patients develop endocrine resistance and metastatic breast cancer. Cyclin-dependent kinase inhibitors (CDKi) in combination with an aromatase inhibitor or fulvestrant have demonstrated superior efficacy increasing progression-free survival, with a safe toxicity profile, in HR+/HER2- metastatic breast cancer patients. CDKi blocks kinases 4/6 ATP-binding domain preventing G1/S cell cycle transition. Despite this, not all patients respond to CDKi and those who respond, finally develop resistance to combination therapy. Different studies, in tumour tissue or cell lines, have tried to elucidate the mechanisms underlying this progression, but there are still no conclusive data. In the last few years, liquid biopsy has contributed relevant information to this knowledge. Liquid biopsy can be performed in real-time, non-invasively and be repeated whenever needed. Circulating tumour material are potential prognostic markers in metastatic luminal breast cancer to determine patient prognosis, monitor disease and treatment selection. The objective of this review is to outline the different studies carried out in HR+ metastatic breast cancer patients treated with CDKi plus endocrine therapy using liquid biopsy approaches looking for possible resistance mechanisms.

scholarly journals FOXA1: A Pioneer of Nuclear Receptor Action in Breast Cancer

Cancers ◽  
2021 ◽  
Vol 13 (20) ◽  
pp. 5205
Author(s):  
Darcie D. Seachrist ◽  
Lindsey J. Anstine ◽  
Ruth A. Keri
Keyword(s):  
Breast Cancer ◽  
Nuclear Receptor ◽  
Cancer Progression ◽  
Endocrine Resistance ◽  
Therapy Response ◽  
Therapeutic Benefit ◽  
Luminal Breast Cancer ◽  
Breast Cancers ◽  
Resistant Disease ◽  
Activation Level

The pioneering function of FOXA1 establishes estrogen-responsive transcriptomes in luminal breast cancer. Dysregulated FOXA1 chromatin occupancy through focal amplification, mutation, or cofactor recruitment modulates estrogen receptor (ER) transcriptional programs and drives endocrine-resistant disease. However, ER is not the sole nuclear receptor (NR) expressed in breast cancers, nor is it the only NR for which FOXA1 serves as a licensing factor. Receptors for androgens, glucocorticoids, and progesterone are also found in the majority of breast cancers, and their functions are also impacted by FOXA1. These NRs interface with ER transcriptional programs and, depending on their activation level, can reprogram FOXA1-ER cistromes. Thus, NR interplay contributes to endocrine therapy response and resistance and may provide a vulnerability for future therapeutic benefit in patients. Herein, we review what is known regarding FOXA1 regulation of NR function in breast cancer in the context of cell identity, endocrine resistance, and NR crosstalk in breast cancer progression and treatment.

scholarly journals Combined Targeting of Estrogen Receptor Alpha and Exportin 1 in Metastatic Breast Cancers

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2397
Author(s):  
Eylem Kulkoyluoglu Cotul ◽  
Qianying Zuo ◽  
Ashlie Santaliz-Casiano ◽  
Ozan Berk Imir ◽  
Ayca Nazli Mogol ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Metabolic Pathways ◽  
Nuclear Export ◽  
Tumor Regression ◽  
Critical Role ◽  
Endocrine Resistance ◽  
Metastatic Breast ◽  
Metabolic Phenotype ◽  
Breast Cancers

The majority of breast cancer specific deaths in women with estrogen receptor positive (ER+) tumors occur due to metastases that are resistant to therapy. There is a critical need for novel therapeutic approaches to achieve tumor regression and/or maintain therapy responsiveness in metastatic ER+ tumors. The objective of this study was to elucidate the role of metabolic pathways that undermine therapy efficacy in ER+ breast cancers. Our previous studies identified Exportin 1 (XPO1), a nuclear export protein, as an important player in endocrine resistance progression and showed that combining selinexor (SEL), an FDA-approved XPO1 antagonist, synergized with endocrine agents and provided sustained tumor regression. In the current study, using a combination of transcriptomics, metabolomics and metabolic flux experiments, we identified certain mitochondrial pathways to be upregulated during endocrine resistance. When endocrine resistant cells were treated with single agents in media conditions that mimic a nutrient deprived tumor microenvironment, their glutamine dependence for continuation of mitochondrial respiration increased. The effect of glutamine was dependent on conversion of the glutamine to glutamate, and generation of NAD+. PGC1α, a key regulator of metabolism, was the main driver of the rewired metabolic phenotype. Remodeling metabolic pathways to regenerate new vulnerabilities in endocrine resistant breast tumors is novel, and our findings reveal a critical role that ERα-XPO1 crosstalk plays in reducing cancer recurrences. Combining SEL with current therapies used in clinical management of ER+ metastatic breast cancer shows promise for treating and keeping these cancers responsive to therapies in already metastasized patients.

scholarly journals Comparison of two targeted ultra-deep sequencing technologies for analysis of plasma circulating tumour DNA in endocrine-therapy-resistant breast cancer patients

2021 ◽  
Author(s):  
Georgios Nteliopoulos ◽  
Karen Page ◽  
Allison Hills ◽  
Karen Howarth ◽  
Warren Emmett ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Endocrine Resistance ◽  
Metastatic Breast ◽  
Predictive Biomarker ◽  
Plasma Samples ◽  
Breast Cancer Patients ◽  
Sequencing Technologies ◽  
Highly Correlated ◽  
Detection Of Mutations ◽  
Circulating Tumour Dna

Abstract Purpose There is growing interest in the application of circulating tumour DNA (ctDNA) as a sensitive tool for monitoring tumour evolution and guiding targeted therapy in patients with cancer. However, robust comparisons of different platform technologies are still required. Here we compared the InVisionSeq™ ctDNA Assay with the Oncomine™ Breast cfDNA Assay to assess their concordance and feasibility for the detection of mutations in plasma at low (< 0.5%) variant allele fraction (VAF). Methods Ninety-six plasma samples from 50 patients with estrogen receptor (ER)-positive metastatic breast cancer (mBC) were profiled using the InVision Assay. Results were compared to the Oncomine assay in 30 samples from 26 patients, where there was sufficient material and variants were covered by both assays. Longitudinal samples were analysed for 8 patients with endocrine resistance. Results We detected alterations in 59/96 samples from 34/50 patients analysed with the InVision assay, most frequently affecting ESR1, PIK3CA and TP53. Complete or partial concordance was found in 28/30 samples analysed by both assays, and VAF values were highly correlated. Excellent concordance was found for most genes, and most discordant calls occurred at VAF < 1%. In longitudinal samples from progressing patients with endocrine resistance, we detected consistent alterations in sequential samples, most commonly in ESR1 and PIK3CA. Conclusion This study shows that both ultra-deep next-generation sequencing (NGS) technologies can detect genomic alternations even at low VAFs in plasma samples of mBC patients. The strong agreement of the technologies indicates sufficient reproducibility for clinical use as prognosic and predictive biomarker.

scholarly journals Evaluation of Sirt1 And Foxo’s In Primary Tumor And Distant Organ Metastasis Invaded By Benign And Highly Metastatic Breast Carcinoma Cells Under In Vitro And In Vivo Conditions.

2021 ◽  
Author(s):  
Sayra Dilmac ◽  
Nilay Kuscu ◽  
Ayse Caner ◽  
Sendegul Yildirim ◽  
Burcak Yoldas ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Primary Tumor ◽  
Metastatic Breast ◽  
Signal Pathways ◽  
Breast Cancers ◽  
Primary Tumors ◽  
Metastatic Breast Carcinoma ◽  
Liver Tissues

Abstract Breast cancer is the second most common cancer in women. In malignant breast cancers, tumor cells have the potential to metastasize to distant organs through the lymphatic system and blood circulation. The aim of this study is to evaluate the expression of SIRT1 and FoxO proteins in metastatic and nonmetastatic breast cancer cells and distant organs metastasis. In our study, SIRT1, p53, p21, and FoxO proteins have been evaluated in metastatic 4TLM and non-metastatic 67NR cell lines by immunocytochemistry in vitro and also in mice breast cancer model in vivo. Cells were orthotopically injected to mammary fat pads of 8-10 weeks old Balb/c female mice. Primary tumor, lung and liver tissues were removed and expressions of these proteins were evaluated by immunohistochemistry, western blot and RT-PCR. In addition, signal pathways that are related to SIRT and FoxO proteins were examined by using IPA core analysis. TCGA database was browsed for investigation of different genes.In primary tumors, SIRT1, p21, p53, E2F1 and FoxO expressions were higher in 67NR compared to 4TLM. In metastatic lung and liver tissues, the expression levels of SIRT1, FoxO1, FoxO3a and FoxO4 proteins were increased in 4TLM compared to 67NR. IPA and TCGA analysis have also revealed that SIRT1 and FoxO proteins are lower in primary tumors, but increased in metastatic stages. In conclusion, in primary tumors SIRT1 and FoxO expressions were decreased in 4TLM compared to 67NR. Moreover, SIRT1 and FoxO, especially expressed in metastatic cells. High level of FoxO expressions in metastatic stages in TNBC patients also supports its association with metastasis. Our findings suggest that SIRT1 and FoxO’s have crucial role in tumor progression metastatic process in breast cancer.

Coagulation factor 5 (F5) is an estrogen-responsive gene in breast cancer cells

2021 ◽  
Author(s):  
Marianne Andresen ◽  
Marit Sletten ◽  
Per-Morten Sandset ◽  
Nina Iversen ◽  
Benedicte Stavik ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Coagulation Factor ◽  
Breast Tumors ◽  
Estrogen Signaling ◽  
Coagulation System ◽  
Breast Cancers ◽  
Breast Cancer Patients ◽  
Er Positive ◽  
Pre Treatment

Most breast cancers express estrogen receptor (ER) where estrogen signaling plays an important role. Cancer contributes to activation of the coagulation system leading to an imbalance in the hemostatic system, and Coagulation factor (F) V, which is a key regulator of blood coagulation, has been shown to be increased in breast tumors. Thus, the molecular association between estrogens and FV was explored. Stimulation with 17-β-estradiol (E2) or 17-β-ethinylestradiol (EE2) resulted in a time- and dose-dependent increase in F5 mRNA and FV protein in ERα positive MCF-7 cells. Pre-treatment with the ER antagonist fulvestrant or knockdown of ERα prior to stimulation with E2 counteracted this effect. Three ERα binding half-sites were identified in the promoter region of the F5 gene in silico. Reporter gene analysis showed that all three half-sites were involved in the estrogen-induced gene regulation in vitro, as the effect was abolished only when all half-sites were mutated. High F5 levels in ER positive breast tumors were associated with increased relapse-free survival of breast cancer patients.

D538G acquired mutation of estrogen receptor (ER) alpha: A novel mechanism of endocrine resistance in metastatic breast cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e11578-e11578
Author(s):  
Ido Wolf ◽  
Keren Merenbakh ◽  
Tami Rubinek ◽  
Lior Soussan-Gutman ◽  
Baruch Klein ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Transcriptional Activity ◽  
Novel Mutation ◽  
Endocrine Resistance ◽  
Metastatic Breast ◽  
Endocrine Treatment ◽  
Growth Factor Signaling ◽  
Development Of Resistance ◽  
Er Positive

e11578 Background: Resistance to endocrine therapy occurs in virtually all patients with ER-positive metastatic breast cancer (MBC) and is attributed to various mechanisms including loss of ER expression, altered activity of coregulators and cross-talk between the ER and growth factor signaling pathways. To our knowledge, acquired mutations of the ER have not been described as mediating endocrine resistance to endocrine treatment. Methods: Deep sequencing of the ER was conducted, as part of a commercially available next-generation sequencing of 182 cancer-related genes, on samples obtained from 10 heavily pre-treated, endocrine resistant patients with ER positive MBC. In one patient, a sample obtained at diagnosis was also available. Mutated ER was cloned and overexpressed in breast cancer cells. Transcriptional activity was tested using estrogen response element (ERE)-Luciferase construct, effects on viability were tested using MTT assays and computerized modeling was used to assess structural effects. Results: A novel mutation resulting in substitution of aspartic acid at position 538 to glycine was identified in 4 of 10 samples. Moreover, in one case in which samples were available prior to and following development of resistance, the D538G mutation was noted only in the latter sample. Structural modeling indicated that the substitution leads to a conformational change in the ligand binding domain which prevents binding of either estrogen or tamoxifen and mimics the conformation of activated receptor. Experiments in cell lines indicated constitutive ligand-independent transcriptional activity of the mutated receptor. Overexpression of the receptor in MCF-7 cells enhanced proliferation and conferred resistance to treatment with tamoxifen and fulvestarnt. Conclusions: We report here a novel mutation D538G of the ER in human breast cancer and demonstrate its role in mediating resistance to endocrine treatment. Our study also indicates, for the first time, acquired mutation of the ER as a novel mechanism of endocrine resistance. Further studies on larger populations and on less selected patients are needed in order to assess the accurate frequency of this novel mutation.

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