scholarly journals Endocrine resistance in hormone-responsive breast cancer: mechanisms and therapeutic strategies

2016 ◽  
Vol 23 (8) ◽  
pp. R337-R352 ◽  
Author(s):  
Conleth G Murphy ◽  
Maura N Dickler
Keyword(s):  
Breast Cancer ◽  
Endocrine Therapy ◽  
Hormone Receptors ◽  
De Novo ◽  
Feedback Inhibition ◽  
Acquired Resistance ◽  
Endocrine Resistance ◽  
Breast Cancers ◽  
Potential Relief ◽  
Rational Therapy

The majority of breast cancers may be considered hormone responsive due to expression of hormone receptors (HR+). Although endocrine therapy is always considered for advanced HR+ breast cancer, the emergence of resistance is inevitable over time and is present from the start in a proportion of patients. In this review, we explore the mechanisms underlyingde novoand acquired resistance to endocrine therapy. We comprehensively review newly approved and emerging therapies that have been developed to counteract specific mechanisms of resistance. We discuss the challenges pertinent to this therapeutic arena including the potential relief of negative regulatory feedback inhibition with compensatory pathway activation and the evolution of molecular changes in HR+ breast cancers during treatment. We discuss strategies to address these challenges in order to develop rational therapy approaches for patients with advanced HR+ breast cancer.

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.

Growth factor signalling and response to endocrine therapy: the Royal Marsden Experience

2005 ◽  
Vol 12 (Supplement_1) ◽  
pp. S113-S117 ◽  
Author(s):  
M Dowsett ◽  
S Johnston ◽  
L-A Martin ◽  
J Salter ◽  
M Hills ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Endocrine Therapy ◽  
Aromatase Inhibitors ◽  
De Novo ◽  
Acquired Resistance ◽  
Poor Response ◽  
Biological Data ◽  
Breast Cancers ◽  
Er Positive ◽  
Almost All

De novo resistance to endocrine therapy is a near-universal feature of oestrogen receptor (ER)- negative breast cancer. Although many ER-positive breast cancers also show no response to tamoxifen or aromatase inhibitors on objective clinical grounds the large majority show reduced proliferation indicating that some oestrogen dependence is present in almost all ER-positive breast cancer. In neoadjuvant studies HER2 positivity is associated with poor response rates to tamoxifen but not aromatase inhibitors, consistent with preclinical models. Acquired resistance to tamoxifen is associated with decreases in ER positivity but most recurrent lesions remain ER-positive. A small proportion of these show increased HER2 expression and in these patients increased phospho-p38 may contribute to the tamoxifen-resistant phenotype. There is an unfortunate paucity of clinical and biological data on acquired resistance to aromatase inhibitors.

Treatment Algorithms for Hormone Receptor–Positive Advanced Breast Cancer: Going Forward in Endocrine Therapy—Overcoming Resistance and Introducing New Agents

2013 ◽  
pp. e28-e36 ◽  
Author(s):  
Stephen R. D. Johnston ◽  
Gaia Schiavon
Keyword(s):  
Breast Cancer ◽  
Growth Factor ◽  
Endocrine Therapy ◽  
De Novo ◽  
Endocrine Resistance ◽  
Growth Factor Receptor ◽  
New Agents ◽  
Treatment Algorithms ◽  
Hormone Receptor Positive ◽  
Survival Pathways

Overcoming de novo or acquired endocrine resistance remains critical to further enhancing the benefit of existing endocrine therapies. Recent progress has been made in understanding the molecular biology associated with acquired endocrine resistance, including adaptive “cross-talk” between ER and various growth factor receptor and cell-signaling pathways. Strategies that combine endocrine therapy with targeted inhibitors of growth factor receptors or cell-survival pathways to further enhance first-line response have largely been disappointing, suggesting that any attempts to prevent endocrine resistance by blocking specific pathways from the outset will be futile. In contrast, success has been seen by selecting patients with acquired endocrine resistance and enhancing response to further endocrine therapy by the addition of mTOR antagonists. Numerous other therapeutics are being evaluated in combination with endocrine therapies based on varying levels of preclinical science to support their use, including inhibitors of PI3K, HDAC, Src, IGFR-1, and CDK4/6. Enriching trial recruitment by molecular profiling of different ER+ subtypes will become increasingly important to maximize any additional benefit that these new agents may bring to current endocrine therapies for breast cancer.

A phase II study of anastrazole and fulvestrant in combination with gefitinib in patients with newly diagnosed ER-positive breast cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 1050-1050
Author(s):  
S. A. Massarweh ◽  
Y. L. Tham ◽  
H. Weiss ◽  
S. Fuqua ◽  
J. Huang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Adverse Events ◽  
Endocrine Therapy ◽  
Phase Ii ◽  
Kinase Inhibitor ◽  
De Novo ◽  
Endocrine Resistance ◽  
Neoadjuvant Endocrine Therapy ◽  
Egfr Inhibition ◽  
Biomarker Analysis

1050 Background: Endocrine therapy for ER+ breast cancer is effective and relatively nontoxic, but is limited by de novo and acquired resistance. Preclinical studies suggest that complete ER blockade along with inhibition of co-expressed growth factor receptors enhances endocrine response and overcomes resistance. Methods: We conducted a phase II trial of combined anastrazole and fulvestrant with gefitinib, an EGFR tyrosine kinase inhibitor, as intial therapy in postmenopausal women with locoregional or metastatic ER+ breast cancer. A tumor core biopsy was done at baseline and after 3 weeks. Patients received treatment for 4 months. Surgery was then offered if the tumor was operable. Primary endpoint was clinical response as defined by RECIST criteria and secondary endpoints were safety/tolerability, complete pathologic response rate (pCR), and biomarker analysis. Planned sample size was 60 patients, but the study closed after 15 patients were enrolled because of poor accrual. Results: Median age at diagnosis was 67 years. Median clinical tumor size was 7 cm and 4 patients had metastases. 11 patients (73%) had ER+/PgR+ tumors and 4 (27%) had ER+/PgR- disease. 3 patients withdraw from the study before response was assessed. Of the12 remaining patients there were 2 complete responses (17%), 5 partial responses (42%), 5 with stable disease (42%), and 2 (17%) with progressive disease. Of the 7 patients who had surgery at 4 months, none had pCR. Most common adverse events were rash in 4 patients, Diarrhea in 4, joint symptoms in 3, and abnormal LFT’s in 3. All adverse events were reversible. Biomarkers, including arrays and Ki67, are pending and will be presented at the meeting. Conclusions: Complete ER blockade using anastrazole and fulvestrant with EGFR inhibition is well-tolerated and has activity in this cohort of patients with relatively advanced ER+ breast cancer. Despite its documented benefit and low toxicity, accrual to neoadjuvant endocrine therapy studies remains poor in the US, largely because of physician hesitance to refer patients for non-chemotherapy studies. More effort is needed to increase physician awareness about the value of endocrine therapy, and to increase accrual to trials that address the question of endocrine resistance. [Table: see text]

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 Neuroglobin: A New Possible Marker of Estrogen-Responsive Breast Cancer

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1986
Author(s):  
Virginia Solar Fernandez ◽  
Marco Fiocchetti ◽  
Manuela Cipolletti ◽  
Marco Segatto ◽  
Paolo Cercola ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Endocrine Therapy ◽  
De Novo ◽  
Ductal Carcinoma ◽  
Strong Association ◽  
Therapeutic Interventions ◽  
Breast Cancer Cell Lines ◽  
Breast Cancers ◽  
Data Set

The expression of the α-subtype of Estrogen Receptor (ERα) characterizes most breast cancers (more than 75%), for which endocrine therapy is the mainstay for their treatment. However, a high percentage of ERα+ breast cancers are de novo or acquired resistance to endocrine therapy, and the definition of new targets for improving therapeutic interventions and the prediction of treatment response is demanding. Our previous data identified the ERα/AKT/neuroglobin (NGB) pathway as a common pro-survival process activated in different ERα breast cancer cell lines. However, no in vivo association between the globin and the malignity of breast cancer has yet been done. Here, we evaluated the levels and localization of NGB in ERα+ breast ductal carcinoma tissue of different grades derived from pre-and post-menopausal patients. The results indicate a strong association between NGB accumulation, ERα, AKT activation, and the G3 grade, while no association with the menopausal state has been evidenced. Analyses of the data set (e.g., GOBO) strengthen the idea that NGB accumulation could be linked to tumor cell aggressiveness (high grade) and resistance to treatment. These data support the view that NGB accumulation, mainly related to ER expression and tumor grade, represents a compensatory process, which allows cancer cells to survive in an unfavorable environment.

scholarly journals Oestrogen receptor negativity in breast cancer: a cause or consequence?

2016 ◽  
Vol 36 (6) ◽  
Author(s):  
Vijaya Narasihma Reddy Gajulapalli ◽  
Vijaya Lakshmi Malisetty ◽  
Suresh Kumar Chitta ◽  
Bramanandam Manavathi
Keyword(s):  
Breast Cancer ◽  
Histone Deacetylases ◽  
Oestrogen Receptor ◽  
De Novo ◽  
Endocrine Resistance ◽  
Dna Methyltransferases ◽  
Breast Cancers ◽  
Cell Of Origin ◽  
Cellular Origin ◽  
Underlying Mechanisms

Endocrine resistance, which occurs either by de novo or acquired route, is posing a major challenge in treating hormone-dependent breast cancers by endocrine therapies. The loss of oestrogen receptor α (ERα) expression is the vital cause of establishing endocrine resistance in this subtype. Understanding the mechanisms that determine the causes of this phenomenon are therefore essential to reduce the disease efficacy. But how we negate oestrogen receptor (ER) negativity and endocrine resistance in breast cancer is questionable. To answer that, two important approaches are considered: (1) understanding the cellular origin of heterogeneity and ER negativity in breast cancers and (2) characterization of molecular regulators of endocrine resistance. Breast tumours are heterogeneous in nature, having distinct molecular, cellular, histological and clinical behaviour. Recent advancements in perception of the heterogeneity of breast cancer revealed that the origin of a particular mammary tumour phenotype depends on the interactions between the cell of origin and driver genetic hits. On the other hand, histone deacetylases (HDACs), DNA methyltransferases (DNMTs), miRNAs and ubiquitin ligases emerged as vital molecular regulators of ER negativity in breast cancers. Restoring response to endocrine therapy through re-expression of ERα by modulating the expression of these molecular regulators is therefore considered as a relevant concept that can be implemented in treating ER-negative breast cancers. In this review, we will thoroughly discuss the underlying mechanisms for the loss of ERα expression and provide the future prospects for implementing the strategies to negate ER negativity in breast cancers.

scholarly journals Oestrogen Non-Genomic Signalling is Activated in Tamoxifen-Resistant Breast Cancer

2019 ◽  
Vol 20 (11) ◽  
pp. 2773 ◽  
Author(s):  
Coralie Poulard ◽  
Julien Jacquemetton ◽  
Olivier Trédan ◽  
Pascale A. Cohen ◽  
Julie Vendrell ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Acquired Resistance ◽  
Endocrine Resistance ◽  
In Vitro Models ◽  
Proximity Ligation Assay ◽  
Breast Cancers ◽  
Cancer Management ◽  
Tamoxifen Resistant

Endocrine therapies targeting oestrogen signalling have significantly improved breast cancer management. However, their efficacy is limited by intrinsic and acquired resistance to treatment, which remains a major challenge for oestrogen receptor α (ERα)-positive tumours. Though many studies using in vitro models of endocrine resistance have identified putative actors of resistance, no consensus has been reached. We demonstrated previously that oestrogen non-genomic signalling, characterized by the formation of the ERα/Src/PI3K complex, is activated in aggressive breast cancers (BC). We wondered herein whether the activation of this pathway is also involved in resistance to endocrine therapies. We studied the interactions between ERα and Src or PI3K by proximity ligation assay (PLA) in in-vitro and in-vivo endocrine therapy-resistant breast cancer models. We reveal an increase in ERα/Src and ERα/PI3K interactions in patient-derived xenografts (PDXs) with acquired resistance to tamoxifen, as well as in tamoxifen-resistant MCF-7 cells compared to parental counterparts. Moreover, no interactions were observed in breast cancer cells resistant to other endocrine therapies. Finally, the use of a peptide inhibiting the ERα–Src interaction partially restored tamoxifen sensitivity in resistant cells, suggesting that such components could constitute promising targets to circumvent resistance to tamoxifen in BC.

scholarly journals PAK4 regulates stemness and progression in endocrine resistant ER-positive metastatic breast cancer

2019 ◽  
Author(s):  
Angélica Santiago-Gómez ◽  
Ilaria Dragoni ◽  
Roisin NicAmhlaoibh ◽  
Elisabeth Trivier ◽  
Verity Sabin ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Metastatic Breast Cancer ◽  
Disease Progression ◽  
Poor Prognosis ◽  
Acquired Resistance ◽  
Endocrine Resistance ◽  
Metastatic Breast ◽  
Breast Cancers ◽  
P21 Activated Kinase

AbstractDespite the effectiveness of endocrine therapies to treat estrogen receptor-positive (ER+) breast tumours, two thirds of patients will eventually relapse due tode novoor acquired resistance to these agents. Cancer Stem-like Cells (CSCs), a rare cell population within the tumour, accumulate after anti-estrogen treatments and are likely to contribute to their failure. Here we studied the role of p21-activated kinase 4 (PAK4) as a promising target to overcome endocrine resistance and disease progression in ER+ breast cancers. PAK4 predicts for resistance to tamoxifen and poor prognosis in 2 independent cohorts of ER+ tumours. We observed that PAK4 strongly correlates with CSC activity in metastatic patient-derived samples irrespective of breast cancer subtype. However, PAK4-driven mammosphere-forming CSC activity increases alongside progression only in ER+ metastatic samples. PAK4 activity increases in ER+ models during acquired resistance to endocrine therapies. Targeting PAK4 with either CRT PAKi, a small molecule inhibitor of PAK4, or with specific siRNAs abrogates CSC activity/self-renewal in clinical samples and endocrine-resistant cells. Together, our findings establish that PAK4 regulates stemness during disease progression and that its inhibition reverses endocrine resistance in ER+ breast cancers.HighlightsPAK4 predicts for failure of endocrine therapies and poor prognosisPAK4 drives stemness and progression in ER+ metastatic breast cancerTargeting PAK4 abrogates breast CSC activity and restores sensitivity to endocrine treatmentsTargeting PAK4 will improve outcome of ER+ breast cancer patientsList of Abbreviations that appeared in abstractCancer Stem-like Cells (CSCs)p21-activated kinase 4 (PAK4)Estrogen Receptor (ER)

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