Molecular Mechanisms of Endocrine Resistance

2018 ◽  
pp. 265-307 ◽  
Author(s):  
Xiaoyong Fu ◽  
Carmine De Angelis ◽  
Jamunarani Veeraraghavan ◽  
C. Kent Osborne ◽  
Rachel Schiff
Keyword(s):  
Molecular Mechanisms ◽  
Endocrine Resistance

scholarly journals The Emerging Role of Extracellular Vesicles in Endocrine Resistant Breast Cancer

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1160
Author(s):  
Giusi La Camera ◽  
Luca Gelsomino ◽  
Amanda Caruso ◽  
Salvatore Panza ◽  
Ines Barone ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Endocrine Therapy ◽  
Extracellular Vesicles ◽  
Molecular Mechanisms ◽  
Endocrine Resistance ◽  
Disease Recurrence ◽  
Estrogen Receptor Α ◽  
Research Area ◽  
Tumor Evolution

Breast cancer is the most common solid malignancy diagnosed in females worldwide, and approximately 70% of these tumors express estrogen receptor α (ERα), the main biomarker of endocrine therapy. Unfortunately, despite the use of long-term anti-hormone adjuvant treatment, which has significantly reduced patient mortality, resistance to the endocrine treatments often develops, leading to disease recurrence and limiting clinical benefits. Emerging evidence indicates that extracellular vesicles (EVs), nanosized particles that are released by all cell types and responsible for local and systemic intercellular communications, might represent a newly identified mechanism underlying endocrine resistance. Unraveling the role of EVs, released by transformed cells during the tumor evolution under endocrine therapy, is still an open question in the cancer research area and the molecular mechanisms involved should be better defined to discover alternative therapeutic approaches to overcome resistance. In this review, we will provide an overview of recent findings on the involvement of EVs in sustaining hormonal resistance in breast cancer and discuss opportunities for their potential use as biomarkers to monitor the therapeutic response and disease progression.

Molecular mechanisms of endocrine resistance and their implication in the therapy of breast cancer

2009 ◽  
Vol 1795 (1) ◽  
pp. 62-81 ◽  
Author(s):  
Marinella Zilli ◽  
Antonino Grassadonia ◽  
Nicola Tinari ◽  
Alessia Di Giacobbe ◽  
Simona Gildetti ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Molecular Mechanisms ◽  
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 Potential Molecular Mechanisms of Chaihu-Shugan-San in Treatment of Breast Cancer Based on Network Pharmacology

2020 ◽  
Vol 2020 ◽  
pp. 1-9 ◽  
Author(s):  
Kunmin Xiao ◽  
Kexin Li ◽  
Sidan Long ◽  
Chenfan Kong ◽  
Shijie Zhu
Keyword(s):  
Breast Cancer ◽  
Chinese Medicine ◽  
Traditional Chinese Medicine ◽  
Molecular Mechanisms ◽  
Endocrine Resistance ◽  
Protein Domain ◽  
Network Pharmacology ◽  
Complementary And Alternative Therapy ◽  
Cell Substrate ◽  
Catabolic Process

Breast cancer is one of the most common cancers endangering women’s health all over the world. Traditional Chinese medicine is increasingly recognized as a possible complementary and alternative therapy for breast cancer. Chaihu-Shugan-San is a traditional Chinese medicine prescription, which is extensively used in clinical practice. Its therapeutic effect on breast cancer has attracted extensive attention, but its mechanism of action is still unclear. In this study, we explored the molecular mechanism of Chaihu-Shugan-San in the treatment of breast cancer by network pharmacology. The results showed that 157 active ingredients and 8074 potential drug targets were obtained in the TCMSP database according to the screening conditions. 2384 disease targets were collected in the TTD, OMIM, DrugBank, GeneCards disease database. We applied the Bisogenet plug-in in Cytoscape 3.7.1 to obtain 451 core targets. The biological process of gene ontology (GO) involves the mRNA catabolic process, RNA catabolic process, telomere organization, nucleobase-containing compound catabolic process, heterocycle catabolic process, and so on. In cellular component, cytosolic part, focal adhesion, cell-substrate adherens junction, and cell-substrate junction are highly correlated with breast cancer. In the molecular function category, most proteins were addressed to ubiquitin-like protein ligase binding, protein domain specific binding, and Nop56p-associated pre-rRNA complex. Besides, the results of the KEGG pathway analysis showed that the pathways mainly involved in apoptosis, cell cycle, transcriptional dysregulation, endocrine resistance, and viral infection. In conclusion, the treatment of breast cancer by Chaihu-Shugan-San is the result of multicomponent, multitarget, and multipathway interaction. This study provides a certain theoretical basis for the treatment of breast cancer by Chaihu-Shugan-San and has certain reference value for the development and application of new drugs.

Phase II study of the multikinase inhibitor dovitinib (TKI258) or placebo in combination with fulvestrant in postmenopausal, endocrine resistant HER2-/HR+ breast cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS1148-TPS1148
Author(s):  
Fabrice Andre ◽  
Richard Greil ◽  
Neelima Denduluri ◽  
Alejandro Javier Yovine ◽  
Cathy Reddick ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Endocrine Therapy ◽  
Phase Ii ◽  
Molecular Mechanisms ◽  
Locally Advanced ◽  
Endocrine Resistance ◽  
Metastatic Breast ◽  
Predictive Biomarkers ◽  
Her2 Breast Cancer ◽  
Patient Reported

TPS1148 Background: Overcoming endocrine resistance is a critical goal in the treatment of hormone receptor−positive (HR+) breast cancer. Molecular mechanisms associated with endocrine resistance include adaptive “cross-talk” between the estrogen receptor and the fibroblast growth factor receptor (FGFR). Up to 8% of HR+/HER2- breast cancer patients (pts) have amplification of the FGFR1 gene, which is associated with resistance to endocrine therapy but can be overcome via FGFR1 inhibition in preclinical models. Dovitinib is a potent FGF, VEGF, and PDGF receptor tyrosine kinase inhibitor that demonstrated antitumor activity in heavily pretreated breast cancer pts with FGF pathway amplification (FGFR1, FGFR2, or ligand FGF3; Andre et al, ASCO 2011). Dovitinib may reverse resistance to endocrine therapy related to FGF-pathway amplification and is studied here to determine if it can improve outcomes when combined with fulvestrant. Methods: Postmenopausal HER2-/HR+ locally advanced or metastatic breast cancer pts (N»150) progressing within 12 months of completion of adjuvant endocrine therapy or after ≤ 1 prior endocrine therapy in the advanced setting will be enrolled in this multicenter, randomized, double blind, placebo controlled, phase II trial. Pts will prospectively undergo molecular screening to enrich for FGF-amplification (FGFR1, FGFR2, or FGF3 amplification by qPCR; 45 amplified and 30 non-amplified pts per arm). Pts will be randomized 1:1 to receive fulvestrant (500 mg q4w [with an additional dose 2 wks after the initial dose]) in combination with oral dovitinib (500 mg, 5 days on/2 days off) or placebo until disease progression, unacceptable toxicity, or death. The primary endpoint is progression-free survival, with tumor assessments performed q8w. Secondary endpoints include overall response rate per RECIST v1.1, duration of response, overall survival, ECOG performance status and patient reported outcome scores over time, and safety. The pharmacodynamic effect of dovitinib on FGFR-associated angiogenic pathways in tumor specimens and potential predictive biomarkers of response to dovitinib will be explored.

scholarly journals Coordinate Enhancer Reprogramming by GATA3 and AP1 Promotes Phenotypic Plasticity to Achieve Breast Cancer Endocrine Resistance

2019 ◽  
Author(s):  
Mingjun Bi ◽  
Zhao Zhang ◽  
Pengya Xue ◽  
Karen Hernandez ◽  
Hu Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Phenotypic Plasticity ◽  
Molecular Mechanisms ◽  
Endocrine Resistance ◽  
Therapy Resistance ◽  
Differentiation Markers ◽  
Functional Studies ◽  
Genome Wide ◽  
Anticancer Treatment ◽  
Gain Loss

ABSTRACTAcquired therapy resistance is a major problem for anticancer treatment, yet the underlying molecular mechanisms remain unclear. Using an established breast cancer cellular model for endocrine resistance, we show that hormone resistance is associated with enhanced phenotypic plasticity, indicated by a general downregulation of luminal/epithelial differentiation markers and upregulation of basal/mesenchymal invasive markers. Our extensive omics studies, including GRO-seq on enhancer landscapes, demonstrate that the global enhancer gain/loss reprogramming driven by the differential interactions between ERα and other oncogenic transcription factors (TFs), predominantly GATA3 and AP1, profoundly alters breast cancer transcriptional programs. Our functional studies in multiple biological systems including culture and xenograft models of MCF7 and T47D lines support a coordinate role of GATA3 and AP1 in enhancer reprogramming that promotes phenotypic plasticity and endocrine resistance. Collectively, our study implicates that changes in TF-TF and TF-enhancer interactions can lead to genome-wide enhancer reprogramming, resulting in transcriptional dysregulations that promote plasticity and cancer therapy-resistance progression.

scholarly journals Endocrine-Resistant Breast Cancer: Mechanisms and Treatment

Breast Care ◽  
2020 ◽  
Vol 15 (4) ◽  
pp. 347-354
Author(s):  
Andreas D. Hartkopf ◽  
Eva-Maria Grischke ◽  
Sara Y. Brucker
Keyword(s):  
Breast Cancer ◽  
Molecular Mechanisms ◽  
Acquired Resistance ◽  
Endocrine Resistance ◽  
Optimal Combination ◽  
Endocrine Treatment ◽  
Esr1 Gene ◽  
Pi3k Inhibition ◽  
Estrogen Receptor Positive ◽  
Positive Breast Cancer

Background: Endocrine treatment is one of the most effective therapies for estrogen receptor-positive breast cancer. However, most tumors will develop resistance to endocrine therapy as the cancer progresses. This review focuses on the mechanisms and markers of endocrine-resistant breast cancer. In addition, current and future strategies to overcome endocrine resistance are discussed. Summary: Several molecular mechanisms of endocrine resistance have been identified, including alterations in the ESR1 gene or in the PIK3CA/mTOR pathway. Meanwhile, CDK4/6, mTOR, and PI3K inhibition have shown to improve the efficacy of endocrine treatment and new promising approaches are being developed. Key Message: Overcoming primary or acquired resistance to endocrine treatment remains a major challenge. Since the molecular mechanisms of endocrine resistance are manifold, optimal combination and sequencing strategies will have to be developed in the future.

scholarly journals Steroid Receptor Signallings as Targets for Resveratrol Actions in Breast and Prostate Cancer

2019 ◽  
Vol 20 (5) ◽  
pp. 1087 ◽  
Author(s):  
Francesca De Amicis ◽  
Adele Chimento ◽  
Francesca Montalto ◽  
Ivan Casaburi ◽  
Rosa Sirianni ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Steroid Receptors ◽  
Endocrine Resistance ◽  
Bioactive Compound ◽  
Therapy Resistance ◽  
Specific Gene ◽  
Resistant Disease ◽  
Combination Strategies

Extensive research over the past 25 years in hormone-dependent cancers, such as breast cancer and prostate cancer, has identified the molecular mechanisms driven by steroid receptors, elucidating the interplay between genomic and non-genomic steroid receptors mechanism of action. Altogether, these mechanisms create the specific gene expression programs that contribute to endocrine therapy resistance and cancer progression. These findings, on the bidirectional molecular crosstalk between steroid and growth factor receptors pathways in endocrine resistance, suggest the use of multi-target inhibitors together with endocrine therapies, for treating resistant disease. In this review we will discuss the novel understanding on the chemopreventive and anti-cancer activities of Resveratrol (3,5,4′-trihydroxy-stilbene) (RSV), a phytoalexin found in grapes acting on a plethora of targets. We will highlight Resveratrol effect on steroid receptors signalling and its potential use in the treatment of hormone-dependent cancer. Understanding the molecular mechanisms by which the bioactive compound influences cancer cell behaviour, by interfering with steroid receptors functional activity, will help to advance the design of combination strategies to increase the rate of complete and durable clinical response in patients.

scholarly journals Heregulin Drives Endocrine Resistance by Altering IL-8 Expression in ER-Positive Breast Cancer

2020 ◽  
Vol 21 (20) ◽  
pp. 7737
Author(s):  
Adriana Papadimitropoulou ◽  
Luciano Vellon ◽  
Ella Atlas ◽  
Travis Vander Steen ◽  
Elisabet Cuyàs ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Nuclear Localization ◽  
Transcriptional Activation ◽  
Neutralizing Antibodies ◽  
Molecular Mechanisms ◽  
Endocrine Resistance ◽  
Extracellular Milieu ◽  
Her2 Breast Cancer ◽  
N Terminus ◽  
Mcf 7

Sustained HER2/HER3 signaling due to the overproduction of the HER3 ligand heregulin (HRG) is proposed as a key contributor to endocrine resistance in estrogen receptor-positive (ER+) breast cancer. The molecular mechanisms linking HER2 transactivation by HRG-bound HER3 to the acquisition of a hormone-independent phenotype in ER+ breast cancer is, however, largely unknown. Here, we explored the possibility that autocrine HRG signaling drives cytokine-related endocrine resistance in ER+ breast cancer cells. We used human cytokine antibody arrays to semi-quantitatively measure the expression level of 60 cytokines and growth factors in the extracellular milieu of MCF-7 cells engineered to overexpress full-length HRGβ2 (MCF-7/HRG cells). Interleukin-8 (IL-8), a chemokine closely linked to ER inaction, emerged as one the most differentially expressed cytokines. Cytokine profiling using structural deletion mutants lacking both the N-terminus and the cytoplasmic-transmembrane region of HRGβ2—which is not secreted and cannot transactivate HER2—or lacking a nuclear localization signal at the N-terminus—which cannot localize at the nucleus but is actively secreted and transactivates HER2—revealed that the HRG-driven activation of IL-8 expression in ER+ cells required HRG secretion and transactivation of HER2 but not HRG nuclear localization. The functional blockade of IL-8 with a specific antibody inversely regulated ERα-driven transcriptional activation in endocrine-sensitive MCF-7 cells and endocrine-resistant MCF-7/HRG cells. Overall, these findings suggest that IL-8 participates in the HRG-driven endocrine resistance program in ER+/HER2- breast cancer and might illuminate a potential clinical setting for IL8- or CXCR1/2-neutralizing antibodies.

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