scholarly journals OR12-07 Full Antagonism of Breast Cancer Cell Proliferation Can Result from Many Ligand-Induced Conformational Distortions of the Estrogen Receptor Ligand Binding Domain

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Jerome Nwachukwu ◽  
Jian Min ◽  
Sathish K Srinivasan ◽  
Erumbi Rangarajan ◽  
Valeria Sanabria Guillen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Ligand Binding ◽  
Estrogen Receptor Alpha ◽  
Side Chain ◽  
Breast Cancers ◽  
Core Element ◽  
Helix 12 ◽  
F Ring ◽  
Regulated Gene Expression

Abstract Although most estrogen receptor alpha (ERα)-positive breast cancers initially respond well to endocrine therapies using aromatase inhibitors (AIs) or antiestrogens, after varying time periods the cancer frequently recurs as metastatic disease. A significant fraction of these recurrences are driven by ERs that have acquired activating mutations in their ligand binding domains (LBDs), giving them constitutive activity and thus resistance to AIs. Because these mutations also reduce the affinity and potency of SERMs and SERDs, expanded efforts have been made to vary the structure of antiestrogens to make them more potent. Typical antiestrogens are comprised of a core element that binds securely in the ligand binding pocket and from which extends a single ring (ring E) having a side chain that sterically interferes with the position of helix-12 by direct antagonism, reorienting it so that it occludes the activation function 2 (AF2) hydrophobic groove for coactivator binding. Through structural studies, we found that bridged oxabicycloheptene-sulfonamide (OBHS-N) core ligands have two rings (E and F) that can be poised to engage in both “direct antagonism” and “indirect antagonism”, the latter of which disrupts the orientation of helix-12 by impinging on helix-11 and the helix-11–12 loop. In this study, we have placed typical antiestrogen side chains on either the E or the F ring of OBHS-N core ligands and characterized their activities in ERα-positive breast cancer cells. All compounds have full antiproliferative activity and reverse estrogen-regulated gene expression, with the antiproliferative potency of each type of side chain having a distinct preference for E- vs F-ring attachment. Conformational analysis using a multiplexed coregulator peptide interaction assay shows that compounds with an E-ring substitution have interaction profiles similar to 4-hydroxytamoxifen and fulvestrant, whereas the F-ring substitution gives a very different pattern, suggesting that the antagonist activity of the two classes rely on different sets of coregulator proteins. A large number of high resolution (better than 2 Å) X-ray crystal structures reveal that this set of novel ER antagonists disrupt the conformation of the ER LBD in a variety of ways, several of which are distinct from those seen with previous antiestrogens such as Tamoxifen and Fulvestrant. Our findings expand design concepts by which ERα ligands can block the activity of this receptor and illustrate how direct and indirect modes of ER antagonism can be combined to facilitate the development of more efficacious antiestrogens for breast cancer treatment and possibly for regulating ER-mediated activities in other estrogen target tissues.

scholarly journals The SERM/SERD Bazedoxifene Disrupts ESR1 Helix 12 to Overcome Acquired Hormone Resistance in Breast Cancer Cells

2018 ◽  
Author(s):  
Sean W. Fanning ◽  
Rinath Jeselsohn ◽  
Venkatasubramanian Dharmarajan ◽  
Christopher G. Mayne ◽  
Mostafa Karimi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Ligand Binding ◽  
Hormone Replacement ◽  
Acquired Resistance ◽  
Metastatic Breast ◽  
Binding Domain ◽  
Ligand Binding Domain ◽  
Breast Cancers ◽  
Helix 12

AbstractAcquired resistance to endocrine therapy remains a significant clinical burden for breast cancer patients. Somatic mutations in theESR1(estrogen receptor alpha (ERα) gene ligand-binding domain (LBD) represent a recognized mechanism of acquired resistance. Antiestrogens with improved efficacy versus tamoxifen might overcome the resistant phenotype in ER+ breast cancers. Bazedoxifene (BZA) is a potent antiestrogen that is clinically approved for use in hormone replacement therapies. We find BZA possesses improved inhibitory potency against the Y537S and D538G ERα mutants compared to tamoxifen and has additional inhibitory activity in combination with the CDK4/6 inhibitor palbociclib. In addition, comprehensive biophysical and structural biology studies show that BZA’s selective estrogen receptor degrading (SERD) properties that override the stabilizing effects of the Y537S and D538G ERα mutations.SignificanceBazedoxifene (BZA) is a potent orally available antiestrogen that is clinically approved for use in hormone replacement therapy (DUAVEE). We explore the efficacy of BZA to inhibit activating somatic mutants of ERα that can arise in metastatic breast cancers after prolonged exposure to aromatase inhibitors or tamoxifen therapy. Breast cancer cell line, biophysical, and structural data show that BZA disrupts helix 12 of the ERα ligand binding domain to achieve improved potency against Y537S and D538G somatic mutants compared to 4-hydroxytamoxifen.

scholarly journals The SERM/SERD bazedoxifene disrupts ESR1 helix 12 to overcome acquired hormone resistance in breast cancer cells

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Sean W Fanning ◽  
Rinath Jeselsohn ◽  
Venkatasubramanian Dharmarajan ◽  
Christopher G Mayne ◽  
Mostafa Karimi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Estrogen Receptor Alpha ◽  
Hormone Replacement ◽  
Acquired Resistance ◽  
Breast Cancers ◽  
Breast Cancer Patients ◽  
Inhibitory Potency ◽  
Clinical Burden ◽  
Helix 12

Acquired resistance to endocrine therapy remains a significant clinical burden for breast cancer patients. Somatic mutations in the ESR1 (estrogen receptor alpha (ERα)) gene ligand-binding domain (LBD) represent a recognized mechanism of acquired resistance. Antiestrogens with improved efficacy versus tamoxifen might overcome the resistant phenotype in ER +breast cancers. Bazedoxifene (BZA) is a potent antiestrogen that is clinically approved for use in hormone replacement therapies. We found that BZA possesses improved inhibitory potency against the Y537S and D538G ERα mutants compared to tamoxifen and has additional inhibitory activity in combination with the CDK4/6 inhibitor palbociclib. In addition, comprehensive biophysical and structural biology studies show BZA’s selective estrogen receptor degrading (SERD) properties that override the stabilizing effects of the Y537S and D538G ERα mutations.

scholarly journals Dual-mechanism estrogen receptor inhibitors expand the repertoire of anti-hormone therapy for breast cancer

2020 ◽  
Author(s):  
Jian Min ◽  
Jerome C. Nwachukwu ◽  
Sathish Srinivasan ◽  
Erumbi S. Rangarajan ◽  
Charles C. Nettles ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Ligand Binding ◽  
Targeted Therapies ◽  
De Novo ◽  
Binding Pocket ◽  
Side Chain ◽  
Ligand Binding Pocket ◽  
Single Mechanism ◽  
Dual Mechanism

ABSTRACTTamoxifen and fulvestrant are currently two major approved estrogen receptor-α (ER)-targeted therapies for breast cancer, but resistance to their antagonistic actions often develops. Efforts to improve ER-targeted therapies have relied upon a single mechanism, where ligands with a single side chain on the ligand core that extends outward from the ligand binding pocket to directly displace helix (h)12 in the ER ligand-binding domain (LBD), blocking the LBD interaction with transcriptional coactivators that drive proliferation. Here, we describe ER inhibitors that block estrogen-induced proliferation through two distinct structural mechanisms by combining a side chain for direct antagonism with a bulky chemical group that causes indirect antagonism by distorting structural epitopes inside the ligand binding pocket. These dual-mechanism ER inhibitors (DMERIs) fully antagonize the proliferation of wild type ER-positive breast cancer cells and cells that have become resistant to tamoxifen and fulvestrant through activating ER mutations and de novo mechanisms such as overactive growth factor signaling. Conformational probing studies highlight marked differences that distinguish the dual mechanism inhibitors from current standard of care single-mechanism antiestrogens, and crystallographic analyses reveal that they disrupt the positioning of h11 and h12 in multiple ways. Combining two chemical targeting approaches into a single ligand thus provides a flexible platform for next generation ER-targeted therapies.

scholarly journals Increased expression of the estrogen receptor alpha, ESR1, in the tumors of breast cancer patients treated with trastuzumab.

2020 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Estrogen Receptor Alpha ◽  
Estrogen Receptor Α ◽  
Needle Aspiration ◽  
Breast Cancers ◽  
Breast Cancer Patients ◽  
Primary Tumors ◽  
Transcriptional Induction ◽  
Selection Of

Hormones function as growth factors, and estrogen provides growth signals to support and induce the proliferation of breast cancers (1-3). This is the basis of the use of endocrine therapies (4, 5) including tamoxifen and letrozole as first-line treatment for patients with breast cancer. We found through mining published microarray and multiplexed gene expression profiling datasets that the estrogen receptor α (ESR1) was among the genes most differentially expressed in the primary tumors and fine needle aspiration-isolated tumor cells of patients with breast cancer treated with trastuzumab. However, estrogen receptor α was expressed at higher rather than lower levels in the tumors of trastuzumab-treated patients. These data, obtained through blind, systems-level analysis of published microarray data (6-8), suggest that trastuzumab administration in patients with breast cancer is associated with transcriptional induction of the estrogen receptor or selection of tumor clones with high expression of ESR1.

scholarly journals RASSF1A-Mediated Suppression of Estrogen Receptor Alpha (ERα)-Driven Breast Cancer Cell Growth Depends on the Hippo-Kinases LATS1 and 2

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 2868
Author(s):  
Sven Roßwag ◽  
Jonathan P. Sleeman ◽  
Sonja Thaler
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Tumor Suppressor ◽  
Estrogen Receptor Alpha ◽  
Molecular Mechanisms ◽  
Hippo Pathway ◽  
Hippo Signaling ◽  
Breast Cancers ◽  
Receptor Alpha ◽  
And Function

Around 70% of breast cancers express the estrogen receptor alpha (ERα). This receptor is of central importance for breast cancer development and estrogen-dependent tumor growth. However, the molecular mechanisms that are responsible for the control of ERα expression and function in the context of breast carcinogenesis are complex and not fully understood. In previous work, we have demonstrated that the tumor suppressor RASSF1A suppresses estrogen-dependent growth of breast cancer cells through a complex network that keeps ERα expression and function under control. We observed that RASSF1A mediates the suppression of ERα expression through modulation of the Hippo effector Yes-associated protein 1 (YAP1) activity. Here we report that RASSF1A-mediated alteration of YAP1 depends on the Hippo-kinases LATS1 and LATS2. Based on these results, we conclude that inactivation of RASSF1A causes changes in the function of the Hippo signaling pathway and altered activation of YAP1, and as a consequence, increased expression and function of ERα. Thus, the inactivation of RASSF1A might constitute a fundamental event that supports the initiation of ERα-dependent breast cancer. Furthermore, our results support the notion that the Hippo pathway is important for the suppression of luminal breast cancers, and that the tumor-suppressor function of RASSF1A depends on LATS1 and LATS2.

scholarly journals Inhibition of estrogen receptor signaling

2005 ◽  
Vol 8 (3) ◽  
Author(s):  
E. M. Rosen ◽  
S. Fan
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Estrogen Receptor Alpha ◽  
Dietary Factors ◽  
Type I ◽  
Breast Cancers ◽  
Human Breast ◽  
Estrogen Receptor Signaling ◽  
Reduce Breast Cancer Risk ◽  
Pharmacologic Agents

The estrogen receptor-alpha (ER-α) is a Type I nuclear receptor that is over-expressed in the majority of human breast cancers and plays a significant role in the development and progression of these cancers. As estrogen plays important roles in the etiology of breast cancer and the growth of established ER-α expressing cancers, intense interest has been generated in understanding the mechanisms by which ER-α signaling is regulated physiologically and using this knowledge to develop interventions to inhibit ER-α signaling. These efforts have met with some success in the development of pharmacologic agents that can reduce breast cancer risk, prevent recurrence of established cancers, and treat advanced cancers with considerably less side effects than cytotoxic chemotherapy. Here, we will review some of the mechanisms that operate to inhibit ER-α signaling and describe how pharmacologic agents and dietary factors interact with ER-α to block its activity. In the process of reviewing these mechanisms, we will highlight their clinical implications.

Estrogen receptor beta in breast cancer.

2002 ◽  
pp. 1-13 ◽  
Author(s):  
C Palmieri ◽  
G J Cheng ◽  
S Saji ◽  
M Zelada-Hedman ◽  
A W√§rri ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Estrogen Receptor Alpha ◽  
Estrogen Receptor Beta ◽  
Normal Growth ◽  
Breast Cancers ◽  
Proliferating Cells ◽  
Malignant Breast ◽  
Novel Target ◽  
Receptor Beta

Estrogen is essential for normal growth and differentiation in the mammary gland. It also supports growth of approximately 50% of primary breast cancers. For this reason, removal of estrogen or blocking of its action with the anti-estrogen, tamoxifen, is the main treatment for estrogen receptor alpha (ERalpha)-positive tumors. In 1996, when oncologists became aware of a second ER, ERbeta, there was some doubt as to whether this receptor would be of importance in breast cancer because the clinical consensus was that responsiveness to tamoxifen is related to the presence of ERalpha in breast cancer. Today we know that ERalpha and ERbeta have distinct cellular distributions, regulate separate sets of genes and can oppose each other's actions on some genes. We also know that ERbeta is widely expressed in both the normal and malignant breast and that there are proliferating cells in the breast which express ERbeta. In this review we summarize what is known about ERbeta in breast cancer and examine the possibility that ERbeta-selective ligands may well represent a useful class of pharmacological tools with a novel target, namely proliferating cells expressing ERbeta.

X-ray crystal structure analysis of elacestrant (RAD1901), a novel selective estrogen receptor degrader (SERD), bound to estrogen receptor alpha ligand binding domain.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15647-e15647
Author(s):  
Sean W. Fanning ◽  
Geoffrey Greene ◽  
Maureen G. Conlan
Keyword(s):  
Breast Cancer ◽  
Crystal Structure ◽  
Estrogen Receptor ◽  
Ligand Binding ◽  
Binding Pocket ◽  
Binding Domain ◽  
Ligand Binding Domain ◽  
Ligand Binding Pocket ◽  
X Ray ◽  
Helix 12

e15647 Background: Antiestrogens are a mainstay of treatment for estrogen receptor positive (ER+) breast cancer in both the adjuvant and the advanced/metastatic settings. Elacestrant is a mixed activity selective estrogen receptor (SER) alpha (ERα) antagonist, acting as a SER modulator (SERM) at low doses and a SER degrader (SERD) at high doses. It has shown activity in hormone sensitive wild type (WT) ERα and insensitive estrogen receptor gene 1 (ESR1) mutation-harboring (Y537S and D538G) ERα breast cancer, both in preclinical models and in clinical studies. It also possesses a unique pharmacology compared to other competitive ER antagonists in its ability to cross the blood brain barrier. Competitive ERα antagonists are typically comprised of a core that sits in the ligand binding pocket and an arm that manipulates the structure to achieve SERM or SERD activities. In these molecules, the arm is attached in the same position as the triphenylethylene core of tamoxifen. However, elacestrant possesses a novel site of attachment. As such, we hypothesized that elacestrant adopts an alternative binding orientation in the ERα ligand binding pocket to achieve its unique pharmaceutical profiles. Methods: X-ray crystallography was used to solve a co-crystal structure of elacestrant in complex with WT ERα ligand binding domain to 2Å. Results: Overall, elacestrant promotes the formation of a canonical ERα ligand binding domain antagonist conformation, whereby helix 12 (H12) is docked into the activating function-2 cleft. However, elacestrant adopts a novel vector in the ERα ligand binding pocket that places it in close proximity to helix 12. As a result, it forms a bifurcated hydrogen bond that is not observed in other competitive antiestrogens and samples a chemical space known to increase H12 mobility and induce SERD activity. This novel vector also places it near positions 537 and 538, the two most common sites of somatic mutation. Conclusions: The high-resolution x-ray crystal structure of elacestrant suggests that the unique binding mode it adopts enables novel pharmacology and positions it to achieve potency in the WT and activating somatic ERα mutated breast cancer setting.

Estrogen Receptor Status by Immunohistochemistry Is Superior to the Ligand-Binding Assay for Predicting Response to Adjuvant Endocrine Therapy in Breast Cancer

1999 ◽  
Vol 17 (5) ◽  
pp. 1474-1474 ◽  
Author(s):  
Jennet M. Harvey ◽  
Gary M. Clark ◽  
C. Kent Osborne ◽  
D. Craig Allred
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Clinical Outcome ◽  
Ligand Binding ◽  
Endocrine Therapy ◽  
Binding Assay ◽  
Adjuvant Endocrine Therapy ◽  
Ligand Binding Assay ◽  
Breast Cancers ◽  
Er Status

PURPOSE: Immunohistochemistry (IHC) is a newer technique for assessing the estrogen receptor (ER) status of breast cancers, with the potential to overcome many of the shortcomings associated with the traditional ligand-binding assay (LBA). The purpose of this study was to evaluate the ability of ER status determination by IHC, compared with LBA, to predict clinical outcome—especially response to adjuvant endocrine therapy—in a large number of patients with long-term clinical follow-up. PATIENTS AND METHODS: ER status was evaluated in 1,982 primary breast cancers by IHC on formalin-fixed paraffin-embedded tissue sections, using antibody 6F11 and standard methodology. Slides were scored on a scale representing the estimated proportion and intensity of positive-staining tumor cells (range, 0 to 8). Results were compared with ER values obtained by the LBA in the same tumors and to clinical outcome. RESULTS: An IHC score of greater than 2 (corresponding to as few as 1% to 10% weakly positive cells) was used to define ER positivity on the basis of a univariate cut-point analysis of all possible scores and disease-free survival (DFS) in patients receiving any adjuvant endocrine therapy. Using this definition, 71% of all tumors were determined to be ER-positive by IHC, and the level of agreement with the LBA was 86%. In multivariate analyses of patients receiving adjuvant endocrine therapy alone, ER status determined by IHC was better than that determined by the LBA at predicting improved DFS (hazard ratios/P = 0.474/.0008 and 0.707/.3214, respectively) and equivalent at predicting overall survival (0.379/.0001 and 0.381/.0003, respectively). CONCLUSION: IHC is superior to the LBA for assessing ER status in primary breast cancer because it is easier, safer, and less expensive, and has an equivalent or better ability to predict response to adjuvant endocrine therapy.

scholarly journals Endocrine Resistance in Breast Cancer

2014 ◽  
Vol 2014 ◽  
pp. 1-27 ◽  
Author(s):  
J. M. Dixon
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Disease Resistance ◽  
Estrogen Receptor Alpha ◽  
Endocrine Resistance ◽  
Breast Cancers ◽  
Resistance To Therapy ◽  
Receptor Alpha ◽  
Number Of Patients

Around 70% of all breast cancers are estrogen receptor alpha positive and hence their development is highly dependent on estradiol. While the invention of endocrine therapies has revolusioned the treatment of the disease, resistance to therapy eventually occurs in a large number of patients. This paper seeks to illustrate and discuss the complexity and heterogeneity of the mechanisms which underlie resistance and the approaches proposed to combat them. It will also focus on the use and development of methods for predicting which patients are likely to develop resistance.

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