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 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 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 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.

scholarly journals Identification and Analysis of Estrogen Receptor α Promoting Tamoxifen Resistance-Related lncRNAs

2020 ◽  
Vol 2020 ◽  
pp. 1-10
Author(s):  
Xiulei Zhang ◽  
Shanjun Gao ◽  
Zhen Li ◽  
Wei Wang ◽  
Guangzhi Liu
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Cancer Patients ◽  
Estrogen Receptor Alpha ◽  
Acquired Resistance ◽  
Tamoxifen Resistance ◽  
Estrogen Receptor Α ◽  
Rna Seq ◽  
Breast Cancer Patients ◽  
Mcf 7

70-75% breast cancer patients are estrogen receptor alpha positive (ERα+), and the antiestrogen drug tamoxifen has been used for the past three decades. However, in 20-30% of these patients, tamoxifen therapy fails due to intrinsic or acquired resistance. A previous study has showed ERα signaling still exerts significant roles in the development of tamoxifen resistance and several lncRNAs have been demonstrated important roles in tamoxifen resistance. But ERα directly regulated and tamoxifen resistance related lncRNAs remain to be discovered. We reanalyze the published ERα chromatin immunoprecipitation-seq (ChIP-seq) and RNA-seq data of tamoxifen-sensitive (MCF-7/WT) and tamoxifen-resistant (MCF-7/TamR) breast cancer cells. We demonstrate that there are differential ERα recruitment events and the differentials may alert the expression profile in MCF-7/WT and MCF-7/TamR cells. Furthermore, we make an overlap of the ERα binding lncRNAs and differentially expressed lncRNAs and get 49 ERα positively regulated lncRNAs. Among these lncRNAs, the expression levels of AC117383.1, AC144450.1, RP11-15H20.6, and ATXN1-AS1 are negatively correlated with the survival probability of breast cancer patients and ELOVL2-AS1, PCOLCE-AS1, ITGA9-AS1, and FLNB-AS1 are positively correlated. These lncRNAs may be potential diagnosis or prognosis markers of tamoxifen resistance.

scholarly journals Genetic Polymorphisms in the EGFR (R521K) and Estrogen Receptor (T594T) Genes, EGFR and ErbB-2 Protein Expression, and Breast Cancer Risk in Tunisia

2009 ◽  
Vol 2009 ◽  
pp. 1-6 ◽  
Author(s):  
Imen Kallel ◽  
Maha Rebai ◽  
Abdelmajid Khabir ◽  
Nadir R. Farid ◽  
Ahmed Rebaï
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Estrogen Receptor Alpha ◽  
Growth Factor Receptor ◽  
Her2 Overexpression ◽  
Nucleotide Polymorphisms ◽  
Breast Cancers ◽  
Breast Cancer Patients

We evaluated the association of epidermal growth factor receptor (EGFR) 142285G>A (R521K) and estrogen receptor alpha (ESR1) 2014G>A (T594T) single nucleotide polymorphisms with breast cancer risk and prognosis in Tunisian patients. EGFR 142285G>A and ESR1 2014G>A were genotyped in a sample of 148 Tunisian breast cancer patients and 303 controls using PCR-RFLP method. Immunohistochemitsry was used to evaluate the expression levels of EGFR, HER2, ESR1, progesterone receptor and BCL2 in tumors. We found no evidence for an association between EGFR R521K polymorphism and breast cancer risk. However, we found that the homozygous GG (Arg) genotype was more prevalent in patients with lymph node metastasis () and high grade tumors (). The ESR1 2014G allele showed significant association with breast cancer risk (). The GG genotype was associated with HER2 overexpression and this association withstood univariate and multivariate analyses (; , resp.). These data suggest that the R521K might be a prognostic factor, because it correlates with both tumor grade and nodule status. The higher expression of HER2 in ESR1 T594T GG patients suggests the possibility that ESR1 gene polymorphisms accompanied by HER2 expression might influence the pathogenesis of breast cancers.

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.

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.

Hormonal Therapy for the Treatment of Postmenopausal Breast Cancer Patients

2008 ◽  
Vol 21 (1) ◽  
pp. 36-45
Author(s):  
Rebecca E. Greene ◽  
Vivian Tsang
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Postmenopausal Women ◽  
Hormonal Therapy ◽  
Early Stage ◽  
Postmenopausal Breast Cancer ◽  
Breast Cancers ◽  
Breast Cancer Patients ◽  
Hormone Receptor Positive ◽  
Receptor Modulator

Breast cancer is the most common cancer diagnosed and the second leading cause of cancer-related death in women. The majority of breast cancers diagnosed in postmenopausal women are hormone receptor positive and involve therapy with hormonal agents. Tamoxifen, a selective estrogen-receptor modulator, has been the mainstay of hormonal therapy since the 1970s. The more recent approval and success of aromatase inhibitors, such as anastrozole, letrozole, and exemestane, have seen these agents move to the front line of therapy for postmenopausal women with hormone-positive breast cancer in the adjuvant and metastatic settings. Fulvestrant, a selective estrogen receptor— downregulator, provides an additional hormonal therapy with a novel mechanism of action. This article reviews the current literature available regarding the use of these agents for postmenopausal women with early stage or advanced breast cancer.

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