Growth factor signalling and resistance to selective oestrogen receptor modulators and pure anti-oestrogens: the use of anti-growth factor therapies to treat or delay endocrine resistance in breast cancer

2005 ◽  
Vol 12 (Supplement_1) ◽  
pp. S29-S36 ◽  
Author(s):  
R I Nicholson ◽  
I R Hutcheson ◽  
S E Hiscox ◽  
J M Knowlden ◽  
M Giles ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Growth Factor ◽  
Oestrogen Receptor ◽  
De Novo ◽  
Acquired Resistance ◽  
Endocrine Resistance ◽  
Breast Cancer Patients ◽  
Selective Oestrogen Receptor Modulators ◽  
Growth Factor Signalling

De novo insensitivity and acquired resistance to the selective oestrogen receptor modulator tamoxifen and the pure anti-oestrogen fulvestrant (faslodex) severely limit their effectiveness in breast cancer patients. This is a major clinical problem, since each year upward of 1 million women are dispensed anti-oestrogenic drugs. In order to investigate the phenomenon of anti-oestrogen resistance and to rapidly screen drugs that target the resistance mechanism(s), we have previously established several in vitro breast cancer models that have acquired resistance to anti-hormones. Such cells commonly develop an ability to proliferate after approximately 3 months of exposure to 4-hydroxytamoxifen or fulvestrant, despite an initial endocrine-responsive (i.e. growth-suppressive) phase. The current paper explores the role that growth factor signalling plays in the transition of oestrogen receptor-positive endocrine-responsive breast cancer cells to anti-oestrogen resistance or insensitivity and how we might, in the future, most effectively use anti-growth factor therapies to treat or delay endocrine-resistant states.

Acquired resistance to oestrogen deprivation: role for growth factor signalling kinases/oestrogen receptor cross-talk revealed in new MCF-7X model

2005 ◽  
Vol 12 (Supplement_1) ◽  
pp. S85-S97 ◽  
Author(s):  
Cindy M Staka ◽  
Robert I Nicholson ◽  
Julia M W Gee
Keyword(s):  
Growth Factor ◽  
Oestrogen Receptor ◽  
Transcriptional Activity ◽  
Kinase Inhibitor ◽  
Combined Therapy ◽  
Acquired Resistance ◽  
Resistance Mechanism ◽  
Growth Factor Signalling ◽  
Oestrogen Deprivation

In vitro models of long-term oestrogen deprivation utilise increased oestrogen receptor (ER) and are oestrogen hypersensitive, with emerging evidence that growth factor signalling contributes and interacts with ER. However, such models are commonly derived in the presence of serum growth factors that may force the resistance mechanism. Our new in vitro model, MCF-7X, has thus been developed under conditions of both oestrogen and growth factor depletion. ER expression, serine 118 phosphorylation on this receptor and its transcriptional activity were modestly increased compared to the parental MCF-7 cells, although MCF-7X cells were not oestrogen hypersensitive. Faslodex (0.1 μM) partially decreased ER and its transcriptional activity, with associated decreases in serine 118 phosphorylation. Faslodex inhibited MCF-7X growth by 50% for 10 weeks. Classical growth factor receptors did not impact on MCF-7X growth and only a modest contribution for MAP kinase was revealed using PD98059 (25 μM; 35% inhibition for 3 weeks). However, the phosphatidylinositol-3-OH (PI3)-kinase inhibitor LY294002 (5 μM) inhibited MCF-7X growth by 65% for 10 weeks. In contrast to PD98059, LY294002 also partially-inhibited ER transcriptional activity and decreased serine 167 ER phosphorylation. Co-treatment with faslodex plus LY294002 to decrease activity of both serine 118 and 167 proved superior vs the single agents in decreasing ER transcriptional activity and MCF-7X growth (90% inhibition for 25 weeks). However, triple treatment including PD98059 was required to prevent resistance in MCF-7X, an event dependent on maximal depletion of serine 118 phosphorylation and ER transcriptional activity. Kinases clearly contribute in resistance to oestrogen deprivation, cross-talking with ER signalling via AF-1 phosphorylation. While inhibiting each pathway has potential to treat this state, combined therapy targeting all regulators of ER phosphorylation may be required to block subsequent emergence of resistance.

Consensus Statement

2005 ◽  
Vol 12 (Supplement_1) ◽  
pp. S1-S7 ◽  
Author(s):  
J M W Gee ◽  
A Howell ◽  
W J Gullick ◽  
C C Benz ◽  
R L Sutherland ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Growth Factor ◽  
De Novo ◽  
Endocrine Resistance ◽  
Experimental Models ◽  
Model Systems ◽  
Signalling Pathways ◽  
Cancer Data ◽  
Signal Transduction Inhibitors ◽  
Growth Factor Signalling

Anti-hormones (notably tamoxifen), chemotherapy and modern radiotherapeutic approaches are invaluable in the management of breast cancer, and collectively have contributed substantially to the improved survival in this disease. Moreover, there is promise that these successes will continue with the emergence of other endocrine agents (for example, aromatase inhibitors and pure anti-oestrogens). However, de novo and acquired resistance comprises a significant problem with all treatment approaches examined to date. This Workshop aimed to evaluate the contribution made by growth factor signalling pathways in the various resistant states, primarily focusing on resistance to anti-hormonal strategies and spanning experimental models and, where possible, clinical breast cancer data. The successes and limitations of therapeutic targeting of these pathways with various signal transduction inhibitors (STIs) were evaluated in model systems and from emerging clinical trials (including epidermal growth factor receptor inhibitors such as gefitinib). It was concluded that growth factor signalling is an important contributor in the development of endocrine resistance in breast cancer and that use of STIs provides a promising therapeutic strategy for this disease. However, the cancer cell is clearly able to harness alternative growth factor signalling pathways for growth and cell survival in the presence of STI monotherapy and, as a consequence, the efficacy of STIs is likely to be limited by the acquisition of resistance. A number of strategies were proposed from studies in model systems that appeared to enhance anti-tumour actions of existing STI monotherapy, notably including combination therapies targeting multiple pathways. With the increased availability of diverse STIs and improved drug delivery, there is much hope that the more complex therapeutic strategies proposed may ultimately be achievable in clinical practice.

Resistance to endocrine therapy in breast cancer: exploiting estrogen receptor/growth factor signaling crosstalk

2006 ◽  
Vol 13 (Supplement_1) ◽  
pp. S15-S24 ◽  
Author(s):  
Suleiman Massarweh ◽  
Rachel Schiff
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Growth Factor ◽  
Endocrine Therapy ◽  
Acquired Resistance ◽  
Growth Factor Signaling ◽  
Breast Cancer Patients ◽  
Signaling Crosstalk ◽  
Receptor Modulator ◽  
Signal Transduction Inhibitors

Targeting the estrogen receptor (ER) is the oldest form of molecular targeted therapy, and the widespread use of the selective estrogen receptor modulator tamoxifen in breast cancer is responsible for major improvements in cure rates, quality of life, and disease prevention in the last 25 years. Newer forms of endocrine therapy now available for the management of endocrine responsive breast cancer include a new generation of aromatase inhibitors, which lower the estrogen ligand for ER, and pure ER antagonists which destroy the receptor. Despite these recent clinical advances, intrinsic and acquired resistance to these endocrine therapies is still a common feature that limits the success of this therapeutic strategy. Recent research into the molecular biology of ER signaling has revealed a remarkably complex interactive signaling with other growth factor signaling pathways in breast cancer cells, potentially explaining some of the reasons behind endocrine therapy action as well as resistance. This view of a more complex ER signaling system has uncovered new molecular targets which, if present in a cancer cell, might be additionally targeted using various signal transduction inhibitors to overcome or prevent resistance to endocrine therapy. In addition, the dynamic inverse relationship between the expression of ER and growth factor receptors brings more excitement to the potential of restoring ER expression in apparently ER-negative cells by inhibition of growth factor signaling. Ongoing clinical trials of endocrine therapy combined with growth factor pathway inhibitors or their downstream signaling elements promise to further improve the present care for breast cancer patients.

Endocrine Resistance: What Do We Know?

2013 ◽  
pp. e37-e42 ◽  
Author(s):  
Todd W. Miller
Keyword(s):  
Breast Cancer ◽  
Growth Factor ◽  
Tyrosine Kinases ◽  
De Novo ◽  
Early Stage ◽  
Effective Means ◽  
Endocrine Resistance ◽  
Large Body ◽  
Growth Factor Receptor ◽  
Oncogenic Signaling

Adjuvant therapy with antiestrogens targeting estrogen receptor α (ER) signaling prevents disease recurrence in many patients with early-stage ER+ breast cancer. However, a significant number of cases exhibit de novo or acquired endocrine resistance. While other clinical subtypes of breast cancer (HER2+, triple-negative) have disproportionately higher rates of mortality, ER+ breast cancer is responsible for at least as many deaths because it is the most common subtype. Therefore, identifying mechanisms that drive endocrine resistance is a high clinical priority. A large body of experimental evidence indicates that oncogenic signaling pathways underlie endocrine resistance, including growth factor receptor tyrosine kinases (HER2, epidermal growth factor receptor [EGFR], fibroblast growth factor receptor 1/2 [FGFR], insulin-like growth factor-1 receptor [IGF-1R]/ insulin receptor [InsR]), PI3K/AKT/ mTOR, MAPK/ERK, Src, CDK4/CDK6, and ER itself. Combined targeting of ER and such pathways may be the most effective means to combat antiestrogen resistance, and clinical trials testing such strategies show promising results. Herein, we discuss pathways associated with endocrine resistance, biomarkers that may be useful to predict response to targeted agents, and avenues for further exploration to identify strategies for the treatment of patients with endocrine-resistant disease.

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.

scholarly journals Therapeutic targeting of HER2–CB2R heteromers in HER2-positive breast cancer

2019 ◽  
Vol 116 (9) ◽  
pp. 3863-3872 ◽  
Author(s):  
Sandra Blasco-Benito ◽  
Estefanía Moreno ◽  
Marta Seijo-Vila ◽  
Isabel Tundidor ◽  
Clara Andradas ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cannabinoid Receptor ◽  
Acquired Resistance ◽  
Diagnostic Tools ◽  
Breast Cancer Patients ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Positive Breast Cancer

Although human epidermal growth factor receptor 2 (HER2)-targeted therapies have dramatically improved the clinical outcome of HER2-positive breast cancer patients, innate and acquired resistance remains an important clinical challenge. New therapeutic approaches and diagnostic tools for identification, stratification, and treatment of patients at higher risk of resistance and recurrence are therefore warranted. Here, we unveil a mechanism controlling the oncogenic activity of HER2: heteromerization with the cannabinoid receptor CB2R. We show that HER2 physically interacts with CB2R in breast cancer cells, and that the expression of these heteromers correlates with poor patient prognosis. The cannabinoid Δ9-tetrahydrocannabinol (THC) disrupts HER2–CB2R complexes by selectively binding to CB2R, which leads to (i) the inactivation of HER2 through disruption of HER2–HER2 homodimers, and (ii) the subsequent degradation of HER2 by the proteasome via the E3 ligase c-CBL. This in turn triggers antitumor responses in vitro and in vivo. Selective targeting of CB2R transmembrane region 5 mimicked THC effects. Together, these findings define HER2–CB2R heteromers as new potential targets for antitumor therapies and biomarkers with prognostic value in HER2-positive breast cancer.

scholarly journals Roles for miRNAs in endocrine resistance in breast cancer

2015 ◽  
Vol 22 (5) ◽  
pp. R279-R300 ◽  
Author(s):  
Penn Muluhngwi ◽  
Carolyn M Klinge
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Aromatase Inhibitors ◽  
Estrogen Receptor Alpha ◽  
Acquired Resistance ◽  
Endocrine Resistance ◽  
Breast Cancer Patients ◽  
Initial Tumor ◽  
Bona Fide

Therapies targeting estrogen receptor alpha (ERα), including selective ER modulators such as tamoxifen, selective ER downregulators such as fulvestrant (ICI 182 780), and aromatase inhibitors such as letrozole, are successfully used in treating breast cancer patients whose initial tumor expresses ERα. Unfortunately, the effectiveness of endocrine therapies is limited by acquired resistance. The role of microRNAs (miRNAs) in the progression of endocrine-resistant breast cancer is of keen interest in developing biomarkers and therapies to counter metastatic disease. This review focuses on miRNAs implicated as disruptors of antiestrogen therapies, theirbona fidegene targets and associated pathways promoting endocrine resistance.

Modulation of epidermal growth factor receptor in endocrine-resistant, oestrogen receptor-positive breast cancer.

2001 ◽  
pp. 175-182 ◽  
Author(s):  
R I Nicholson ◽  
I R Hutcheson ◽  
M E Harper ◽  
J M Knowlden ◽  
D Barrow ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Oestrogen Receptor ◽  
Kinase Inhibitor ◽  
Growth Factor Receptor ◽  
Independent Manner ◽  
Epidermal Growth

There is an increasing body of evidence demonstrating that growth factor networks are highly interactive with oestrogen receptor (ER) signalling in the control of breast cancer growth. As such, tumour responses to anti- hormones are likely to be a composite of the ER and growth factor inhibitory activity of these agents. The current article examines the modulation of growth factor networks during endocrine response, and presents in vitro and clinical evidence that epidermal growth factor receptor signalling, maintained in either an ER-dependent or -independent manner, is critical to anti- hormonal-resistant breast cancer cell growth. The considerable potential of the epidermal growth factor receptor-selective tyrosine kinase inhibitor, ZD 1839 (Iressa; AstraZeneca) to efficiently treat, and perhaps even prevent, endocrine-resistant breast cancer is highlighted.

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.

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