scholarly journals The immunomodulatory effects of endocrine therapy in breast cancer

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Huanhuan Huang ◽  
Jun Zhou ◽  
Hailong Chen ◽  
Jiaxin Li ◽  
Chao Zhang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Endocrine Therapy ◽  
Checkpoint Inhibitors ◽  
Endocrine Resistance ◽  
Tumor Development ◽  
Immune Microenvironment ◽  
Antitumor Effects ◽  
Estrogen Receptor Modulators ◽  
Cancer Multiple

AbstractEndocrine therapies with SERMs (selective estrogen receptor modulators) or SERDs (selective estrogen receptor downregulators) are standard therapies for patients with estrogen receptor (ER)-positive breast cancer. Multiple small molecule inhibitors targeting the PI3K-AKT-mTOR pathway or CDK4/6 have been developed to be used in combination with anti-estrogen drugs to overcome endocrine resistance. In addition to their direct antitumor effects, accumulating evidence has revealed the tumor immune microenvironment (TIM)-modulating effects of these therapeutic strategies, which have not been properly acknowledged previously. The immune microenvironment of breast tumors plays a crucial role in tumor development, metastasis and treatment response to endocrine therapy and immunotherapy. Therefore, in our current work, we comprehensively review the immunomodulatory effect of endocrine therapy and discuss its potential applications in combination with immune checkpoint inhibitors in breast cancer treatment.

scholarly journals Nuclear Mechanisms Involved in Endocrine Resistance

2021 ◽  
Vol 11 ◽  
Author(s):  
Jürgen Dittmer
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Endocrine Therapy ◽  
Standard Treatment ◽  
Current Knowledge ◽  
Endocrine Resistance ◽  
Estrogen Receptor Α ◽  
Cyclin Dependent Kinase ◽  
Druggable Targets ◽  
Positive Breast Cancer

Endocrine therapy is a standard treatment offered to patients with ERα (estrogen receptor α)-positive breast cancer. In endocrine therapy, ERα is either directly targeted by anti-estrogens or indirectly by aromatase inhibitors which cause estrogen deficiency. Resistance to these drugs (endocrine resistance) compromises the efficiency of this treatment and requires additional measures. Endocrine resistance is often caused by deregulation of the PI3K/AKT/mTOR pathway and/or cyclin-dependent kinase 4 and 6 activities allowing inhibitors of these factors to be used clinically to counteract endocrine resistance. The nuclear mechanisms involved in endocrine resistance are beginning to emerge. Exploring these mechanisms may reveal additional druggable targets, which could help to further improve patients’ outcome in an endocrine resistance setting. This review intends to summarize our current knowledge on the nuclear mechanisms linked to endocrine resistance.

scholarly journals The Central Contributions of Breast Cancer Stem Cells in Developing Resistance to Endocrine Therapy in Estrogen Receptor (ER)-Positive Breast Cancer

Cancers ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 1028 ◽  
Author(s):  
David Rodriguez ◽  
Marc Ramkairsingh ◽  
Xiaozeng Lin ◽  
Anil Kapoor ◽  
Pierre Major ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cells ◽  
Estrogen Receptor ◽  
Cancer Stem Cells ◽  
Hormone Therapy ◽  
Endocrine Therapy ◽  
Endocrine Resistance ◽  
Therapy Resistance ◽  
Breast Cancer Stem Cells ◽  
Er Positive

Breast cancer stem cells (BCSC) play critical roles in the acquisition of resistance to endocrine therapy in estrogen receptor (ER)-positive (ER + ve) breast cancer (BC). The resistance results from complex alterations involving ER, growth factor receptors, NOTCH, Wnt/β-catenin, hedgehog, YAP/TAZ, and the tumor microenvironment. These mechanisms are likely converged on regulating BCSCs, which then drive the development of endocrine therapy resistance. In this regard, hormone therapies enrich BCSCs in ER + ve BCs under both pre-clinical and clinical settings along with upregulation of the core components of “stemness” transcriptional factors including SOX2, NANOG, and OCT4. SOX2 initiates a set of reactions involving SOX9, Wnt, FXY3D, and Src tyrosine kinase; these reactions stimulate BCSCs and contribute to endocrine resistance. The central contributions of BCSCs to endocrine resistance regulated by complex mechanisms offer a unified strategy to counter the resistance. ER + ve BCs constitute approximately 75% of BCs to which hormone therapy is the major therapeutic approach. Likewise, resistance to endocrine therapy remains the major challenge in the management of patients with ER + ve BC. In this review we will discuss evidence supporting a central role of BCSCs in developing endocrine resistance and outline the strategy of targeting BCSCs to reduce hormone therapy resistance.

Tracking endocrine resistance in estrogen-receptor positive breast cancer in ctDNA.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14550-e14550
Author(s):  
Magdalena Meissner ◽  
Rachel Butler ◽  
Angela Claire Casbard ◽  
Margherita Carucci ◽  
Tracie-Ann Madden ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Endocrine Therapy ◽  
Initial Period ◽  
Single Agent ◽  
Endocrine Resistance ◽  
Gene Panel ◽  
Comparable Efficacy ◽  
Liquid Biopsies ◽  
Estrogen Receptor Positive

e14550 Background: Endocrine therapy is the standard of care treatment for patients with estrogen-receptor positive advanced breast cancer, owing to improved tolerability and comparable efficacy to that of cytotoxic chemotherapy. Half of such cancers will progress through first line therapy (primary endocrine resistance) and half will progress after an initial period of disease control (secondary or acquired endocrine resistance). A significant challenge is to test for and identify biomarkers which can guide the likely success of endocrine therapy as a single agent or in combination with small molecule inhibitors.This is particularly challenging where metastatic deposits reside at sites where biopsy is difficult. Potential biomarkers indicative of resistance to endocrine therapy have been identified and can be detected in circulating tumour DNA (ctDNA). CtDNA is shed from tumours and is detectable in a cancer patient’s bloodstream. Information on mutational profiles can guide an oncologist in the selection of targeted therapy in addition to hormonal therapy. Methods: We have analysed formalin-fixed paraffin-embedded(FFPE) tumour samples and longitudinal liquid biopsies from 19 patients who were treated with fulvestrant in combination with a novel inhibitor of the PIK3CA/AKT pathway with next-generation sequencing using a targeted 44-gene panel. Mutations identified using this technique were tracked during the course of treatment using droplet-digital PCR(ddPCR). Results: 57 samples were tested using a 44-gene panel; 19 FFPE tumour samples and matched ctDNA samples were obtained prior therapy and ctDNA samples at disease progression. Mutations detected in PIK3CA, AKT1, ESR1and TP53 genes were trackable in longitudinal ctDNA samples using ddPCR. The association between ctDNA dynamics and outcome will be presented. Conclusions: Multiple mutations that enable the early detection of treatment failure and resistance can be tracked in ctDNA. Investigating the clinical utility of ctDNA is paramount.

scholarly journals Update on the Role of NFκB in Promoting Aggressive Phenotypes of Estrogen Receptor–Positive Breast Cancer

Endocrinology ◽  
2020 ◽  
Vol 161 (10) ◽  
Author(s):  
Emily Smart ◽  
Svetlana E Semina ◽  
Jonna Frasor
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Endocrine Therapy ◽  
Signaling Pathway ◽  
Endocrine Resistance ◽  
Dimethyl Fumarate ◽  
Therapy Resistance ◽  
Molecular Characteristics ◽  
Breast Cancers ◽  
Estrogen Receptor Positive

Abstract The majority of breast cancers are diagnosed as estrogen receptor–positive (ER+) and respond well to ER-targeted endocrine therapy. Despite the initial treatability of ER+ breast cancer, this subtype still accounts for the majority of deaths. This is partly due to the changing molecular characteristics of tumors as they progress to aggressive, metastatic, and frequently therapy resistant disease. In these advanced tumors, targeting ER alone is often less effective, as other signaling pathways become active, and ER takes on a redundant or divergent role. One signaling pathway whose crosstalk with ER has been widely studied is the nuclear factor kappa B (NFκB) signaling pathway. NFκB is frequently implicated in ER+ tumor progression to an aggressive disease state. Although ER and NFκB frequently co-repress each other, it has emerged that the 2 pathways can positively converge to play a role in promoting endocrine resistance, metastasis, and disease relapse. This will be reviewed here, paying particular attention to new developments in the field. Ultimately, finding targeted therapies that remain effective as tumors progress remains one of the biggest challenges for the successful treatment of ER+ breast cancer. Although early attempts to therapeutically block NFκB activity frequently resulted in systemic toxicity, there are some effective options. The drugs parthenolide and dimethyl fumarate have both been shown to effectively inhibit NFκB, reducing tumor aggressiveness and reversing endocrine therapy resistance. This highlights the need to revisit targeting NFκB in the clinic to potentially improve outcome for patients with ER+ breast cancer.

scholarly journals Detection of ESR1 Mutations Based on Liquid Biopsy in Estrogen Receptor-Positive Metastatic Breast Cancer: Clinical Impacts and Prospects

2020 ◽  
Vol 10 ◽  
Author(s):  
Hao Liao ◽  
Wenfa Huang ◽  
Wendi Pei ◽  
Huiping Li
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Endocrine Therapy ◽  
Liquid Biopsy ◽  
Endocrine Resistance ◽  
Metastatic Breast ◽  
Favorable Prognosis ◽  
Sequencing Technologies ◽  
Estrogen Receptor Positive ◽  
Almost All

Endocrine therapy is the main treatment option for estrogen receptor-positive (ER+) breast cancer (BC). Compared with other clinical subtypes, ER+ BC patients usually have a more favorable prognosis. However, almost all ER+ BCpatients develop endocrine resistance and disease progression eventually. A large number of studies based on liquid biopsy suggest that ESR1 mutations may play a key role in this process. For patients with ER+ metastatic BC (MBC), ESR1 is an important prognostic factor and may associate with the resistance to endocrine therapy, like aromatase inhibitors. The advances of sequencing technologies allow us to conduct longitudinal monitoring of disease and unveil the clinical implications of each ESR1 sub-clone in ER+ MBC. Moreover, since the ESR1-related endocrine resistance has not been fully addressed by existing agents, more potent cornerstone drugs should be developed as soon as possible. Herein, we reviewed the recent progress of detecting ESR1 mutations based on liquid biopsy and different sequencing technologies in ER+ MBC and discussed its clinical impacts and prospects.

scholarly journals Molecular Mechanisms of Endocrine Resistance in Estrogen-Positive Breast Cancer

2021 ◽  
Vol 12 ◽  
Author(s):  
Esmael Besufikad Belachew ◽  
Dareskedar Tsehay Sewasew
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Endocrine Therapy ◽  
Molecular Mechanisms ◽  
De Novo ◽  
Endocrine Resistance ◽  
Therapeutic Modality ◽  
Breast Cancers ◽  
Estrogen Receptor Positive ◽  
Positive Breast Cancer

The estrogen receptor is a vital receptor for therapeutic targets in estrogen receptor-positive breast cancer. The main strategy for the treatment of estrogen receptor-positive breast cancers is blocking the estrogen action on estrogen receptors by endocrine therapy but this can be restricted via endocrine resistance. Endocrine resistance occurs due to both de novo and acquired resistance. This review focuses on the mechanisms of the ligand-dependent and ligand-independent pathways and other coregulators, which are responsible for endocrine resistance. It concludes that combinatorial drugs that target different signaling pathways and coregulatory proteins together with endocrine therapy could be a novel therapeutic modality to stop endocrine resistance.

scholarly journals The role of estrogen receptors isoforms in breast cancer

2006 ◽  
Vol 14 (3-4) ◽  
pp. 106-109 ◽  
Author(s):  
Vesna Mandusic ◽  
Dragica Nikolic-Vukosavljevic ◽  
Zora Neskovic-Konstantinovic ◽  
Nikola Tanic ◽  
Dusica Celeketic ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Mrna Expression ◽  
Endocrine Therapy ◽  
Expression Profiles ◽  
Endocrine Resistance ◽  
Inverse Correlation ◽  
Tamoxifen Treatment ◽  
Protein Levels ◽  
Pr Protein

Background: Estrogen and progesterone receptor (ER/PR) status is an accepted predictive marker in breast cancer. It is well known that breast tumors, which are ER(+) are more likely to respond to endocrine therapy. However, certain percentage of ER(+)/PR(+) tumors do not respond to endocrine therapy. Identification of the second estrogen receptor, named estrogen receptor beta (ER?), as well as the existence of numerous isoforms/splice variants of both ER? and ER?, suggests that complex regulation of estrogen action exists. In this study, we analyze does the expression of two ER? isoforms correlates with ER?/PR status. Methods: Sixty samples of primary operable breast carcinomas were analyzed for ER? and PR protein levels and for mRNA expression of two ER? isoforms (ER?1 and ER??5). ER? and PR proteins were measured by classical biochemical techniques, and ER? mRNAs were measured by real-time RT-PCR. Results: Tumors are divided in three groups according to relative level of mRNA for ER?1 and ER??5. We found that there is no correlation of ER?1 mRNA expression with ER? and PR protein levels. We confirmed the existence of inverse correlation of ER??5 with PR and of ER??5 with ER? in the group of postmenopausal patients. In the subsets of tumors defined by ER?/PR status, we found that percentage of tumors, which concomitantly expressed high levels of both transcripts, are parallel with those that do not response to tamoxifen treatment. Conclusion: Inverse correlation of ER? with ER??5 and PR with ER??5isoform suggests that ER??5 may have inhibitory effect on ER? activity in postmenopausal patients. In addition, we point out that determination of expression profiles of ER? and ER? isoforms in the defined groups of patient are necessary for elucidating its involvement in endocrine resistance. .

scholarly journals Intratumoural inflammation and endocrine resistance in breast cancer

2014 ◽  
Vol 22 (1) ◽  
pp. R51-R67 ◽  
Author(s):  
Jill I Murray ◽  
Nathan R West ◽  
Leigh C Murphy ◽  
Peter H Watson
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Endocrine Therapy ◽  
Therapeutic Target ◽  
Estrogen Receptor Alpha ◽  
Endocrine Resistance ◽  
Receptor Alpha ◽  
The Relationship

It is becoming clear that inflammation-associated mechanisms can affect progression of breast cancer and modulate responses to treatment. Estrogen receptor alpha (ERα (ESR1)) is the principal biomarker and therapeutic target for endocrine therapies in breast cancer. Over 70% of patients are ESR1-positive at diagnosis and are candidates for endocrine therapy. However, ESR1-positive tumours can become resistant to endocrine therapy. Multiple mechanisms of endocrine resistance have been proposed, including suppression of ESR1. This review discusses the relationship between intratumoural inflammation and endocrine resistance with a particular focus on inflammation-mediated suppression of ESR1.

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