Selective Estrogen-Receptor Modulators and Antihormonal Resistance in Breast Cancer

2007 ◽  
Vol 25 (36) ◽  
pp. 5815-5824 ◽  
Author(s):  
V. Craig Jordan ◽  
Bert W. O'Malley
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Endometrial Cancer ◽  
Growth Factor Receptor ◽  
The Body ◽  
Breast Cancers ◽  
Estrogen Action ◽  
High Risk Women ◽  
Estrogen Receptor Modulators ◽  
Target Sites

Selective estrogen-receptor (ER) modulators (SERMs) are synthetic nonsteroidal compounds that switch on and switch off target sites throughout the body. Tamoxifen, the pioneering SERM, blocks estrogen action by binding to the ER in breast cancers. Tamoxifen has been used ubiquitously in clinical practice during the last 30 years for the treatment of breast cancer and is currently available to reduce the risk of breast cancer in high-risk women. Raloxifene maintains bone density (estrogen-like effect) in postmenopausal osteoporotic women, but at the same time reduces the incidence of breast cancer in both high- and low-risk (osteoporotic) postmenopausal women. Unlike tamoxifen, raloxifene does not increase the incidence of endometrial cancer. Clearly, the simple ER model of estrogen action can no longer be used to explain SERM action at different sites around the body. Instead, a new model has evolved on the basis of the discovery of protein partners that modulate estrogen action at distinct target sites. Coactivators are the principal players that assemble a complex of functional proteins around the ligand ER complex to initiate transcription of a target gene at its promoter site. A promiscuous SERM ER complex creates a stimulatory signal in growth factor receptor–rich breast or endometrial cancer cells. These events cause drug-resistant, SERM-stimulated growth. The sometimes surprising pharmacology of SERMs has resulted in a growing interest in the development of new selective medicines for other members of the nuclear receptor superfamily. This will allow the precise treatment of diseases that was previously considered impossible.

scholarly journals G-Protein Coupled Estrogen Receptor in Breast Cancer

2019 ◽  
Vol 20 (2) ◽  
pp. 306 ◽  
Author(s):  
Li-Han Hsu ◽  
Nei-Min Chu ◽  
Yung-Feng Lin ◽  
Shu-Huei Kao
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
G Protein ◽  
Growth Factor Receptor ◽  
Tamoxifen Resistance ◽  
Breast Cancers ◽  
Epidermal Growth ◽  
Cancer Tissues ◽  
G Protein Coupled ◽  
Positive Breast Cancer

The G-protein coupled estrogen receptor (GPER), an alternate estrogen receptor (ER) with a structure distinct from the two canonical ERs, being ERα, and ERβ, is expressed in 50% to 60% of breast cancer tissues and has been presumed to be associated with the development of tamoxifen resistance in ERα positive breast cancer. On the other hand, triple-negative breast cancer (TNBC) constitutes 15% to 20% of breast cancers and frequently displays a more aggressive behavior. GPER is prevalent and involved in TNBC and can be a therapeutic target. However, contradictory results exist regarding the function of GPER in breast cancer, proliferative or pro-apoptotic. A better understanding of the GPER, its role in breast cancer, and the interactions with the ER and epidermal growth factor receptor will be beneficial for the disease management and prevention in the future.

Clinical Importance of Estrogen Receptor-β Evaluation in Breast Cancer Patients Treated With Adjuvant Tamoxifen Therapy

2008 ◽  
Vol 26 (22) ◽  
pp. 3727-3734 ◽  
Author(s):  
Naoko Honma ◽  
Rie Horii ◽  
Takuji Iwase ◽  
Shigehira Saji ◽  
Mamoun Younes ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Growth Factor Receptor ◽  
Clinical Importance ◽  
Premenopausal Women ◽  
Adjuvant Tamoxifen ◽  
Positive Staining ◽  
Breast Cancers ◽  
Breast Cancer Patients ◽  
Epidermal Growth

Purpose The clinicopathologic importance of a second estrogen receptor (ER), ER-β, in breast cancers has been intensely studied; however, there is still no real consensus regarding the clinical utility of an ER-β assay, probably because of the lack of standardized methodology, the presence of several ER-β isotypes (ER-β1-5, and so on), and, more importantly, the lack of convincing data on whether the ER-β status provides clinically useful information over what is already provided by the traditional ER-α/progesterone receptor (PR) assay. A large and systematic study is needed to address these important issues. Patients and Methods Archival materials of 442 invasive breast cancers from women treated with adjuvant tamoxifen monotherapy and with a long follow-up period (median, 11.1 years) were subjected to immunohistochemical study using three commercially available anti–ER-β antibodies that detect ER-β1-3 (ER-βN), ER-β1, and ER-βcx (ER-β2). Results Positive staining for ER-βN or ER-β1 was associated with significantly better survival. By contrast, ER-βcx status did not influence survival. In multivariate analysis, ER-β1 status emerged as an independent predictor of recurrence and mortality. ER-β1 status was significantly associated with survival in postmenopausal, but not premenopausal, women. Importantly, ER-β1 positivity was associated with significantly better survival in patients with ER-α–negative/PR-negative or ER-α–negative/PR–negative/human epidermal growth factor receptor 2–negative (triple-negative) tumors, which are widely believed to be hormone unresponsive, have poor prognosis, and require chemotherapy. Conclusion Immunohistochemical examination of ER-β1 in addition to ER-α and PR is clinically important in patients with breast cancer treated with tamoxifen monotherapy. Further studies are needed to confirm our findings.

scholarly journals In silico Molecular Docking Analysis of Imatinib to Target the Marker Proteins of Breast Cancer

2021 ◽  
pp. 29-38
Author(s):  
V. Senthil Kumar ◽  
T. V. Ajay Kumar ◽  
V. Parthasarathy
Keyword(s):  
Breast Cancer ◽  
Communicable Disease ◽  
Mammalian Target Of Rapamycin ◽  
Growth Factor Receptor ◽  
The Body ◽  
Breast Cancers ◽  
Marker Proteins ◽  
Promising Target ◽  
Abnormal Cells ◽  
In Silico Molecular Docking

Cancer is an uncontrolled over growth of abnormal cells elsewhere in the body. It is the second leading cause of death globally due to non communicable disease. Among the various types of cancers, the incidence of breast cancer is next to lung cancer. The most commonly used drugs to treat breast cancer are namely, Anastrozole, Arimidex, Letrozol, Imatinib, Tamoxifen, Raloxifene, Toremifene and so on. The hope is to establish the specificity of the drug Imatinib towards the selective potential breast cancers such as mammalian target of rapamycin, (mTOR), human epidermal growth factor receptor 2 (HER2), estrogen receptor (ER), poly (ADP-Ribose) polymerase (PARP) and phosphoprotein 53 (p53). To identify the promising target, the Schrodinger software was utilized for the study. The study helped to evaluate the pharmacokinetic properties and binding efficiency of Imatinib towards the breast cancer proteins. The results of study showed that the Imatinib exhibited better binding affinities to mTOR and HER2 as compared to ER, PARP and P53 proteins. The present study will be more useful to rationalize the anticancer therapy based on the expression levels of the target protein in the cancer microenvironment.   

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.

The 38th David A. Karnofsky Lecture: The Paradoxical Actions of Estrogen in Breast Cancer—Survival or Death?

2008 ◽  
Vol 26 (18) ◽  
pp. 3073-3082 ◽  
Author(s):  
V. Craig Jordan
Keyword(s):  
Breast Cancer ◽  
Clinical Trials ◽  
Endometrial Cancer ◽  
Adjuvant Therapy ◽  
Response To Therapy ◽  
The Body ◽  
Cancer Drug ◽  
Breast Cancers ◽  
Active Metabolites

During the first David A. Karnofsky Award lecture entitled “Thoughts on Chemical Therapy” in 1970, Sir Alexander Haddow commented about the dramatic regressions observed with estrogen in some breast cancers in postmenopausal women, but regrettably the mechanism was unknown. He was concerned that a cancer-specific target would remain elusive, without tests to predict response to therapy. At that time, I was conducting research for my PhD on an obscure group of estrogen derivatives called nonsteroidal antiestrogens. Antiestrogens had failed to fulfill their promise as postcoital contraceptives and were unlikely to be developed further by the pharmaceutical industry. In 1972, that perspective started to change and ICI 46,474 was subsequently reinvented as the first targeted therapy for breast cancer. The scientific strategy of targeting the estrogen receptor (ER) in the tumor, treating patients with long-term adjuvant therapy, examining active metabolites, and considering chemoprevention all translated through clinical trials to clinical practice during the next 35 years. Hundreds of thousands of women now have enhanced survivorship after their diagnosis of ER-positive breast cancer. However, it was the recognition of selective ER modulation (SERM) that created a new dimension in therapeutics. Nonsteroidal antiestrogens selectively turn on or turn off estrogen target tissues throughout the body. Patient care was immediately affected by the recognition in the laboratory that tamoxifen would potentially increase the growth of endometrial cancer during long-term adjuvant therapy. At that time, a failed breast cancer drug, keoxifene, was found to maintain bone density of rats (estrogenic action) while simultaneously preventing mammary carcinogenesis (antiestrogenic action). Perhaps a SERM used to prevent osteoporosis could simultaneously prevent breast cancer? Keoxifene was renamed raloxifene and became the first SERM for the treatment and prevention of osteoporosis as well as the prevention of breast cancer, but without an increase in endometrial cancer. There the story might have ended had the study of antihormone resistance not revealed a vulnerability of cancer cells that could be exploited in the clinic. The evolution of antihormone resistance over years of therapy reconfigures the survival mechanism of the breast cancer cell, so estrogen no longer is a survival signal but a death signal. Remarkably, remaining tumor tissue is again responsive to continuing antihormone therapy. This new discovery is currently being evaluated in clinical trials but it also solves the mystery mechanism of chemical therapy with estrogen noted by Haddow in the first Karnofsky lecture.

Recent progress in immunotherapy of breast cancer targeting the human epidermal growth factor receptor 2 (HER2)

2021 ◽  
pp. 107815522199163
Author(s):  
Homa Seyedmirzaei ◽  
Mahsa Keshavarz-Fathi ◽  
Sepideh Razi ◽  
Masoumeh Gity ◽  
Nima Rezaei
Keyword(s):  
Breast Cancer ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Growth Factor Receptor ◽  
New Drugs ◽  
Breast Cancers ◽  
Cancer Subtypes ◽  
Drug Conjugates ◽  
Heavy Burden ◽  
Epidermal Growth

Objective Breast cancer is responsible for most of the cancer-induced deaths in women around the world. The current review will discuss different approaches of targeting HER2, an epidermal growth factor overexpressed in 30% of breast cancer cases. Data sources We conducted a search on Pubmed and Scopus databases to find studies relevant to HER2+ breast cancers and targeting HER2 as means of immunotherapy. Out of 1043 articles, 105 studies were included in this review. Data summary As well as the introduction of HER2 and breast cancer subtypes, we discussed various aspects of HER2-targeting immunotherapy including monoclonal antibodies, Antibody-drug conjugates (ADCs), Chimeric Antigen Receptor (CAR) T-cells and vaccines. Conclusions Despite several ways of controlling breast cancer, the need to investigate new drugs and approaches seems to be much significant as this cancer still has a heavy burden on people’s health and survival.

scholarly journals Relationship Between Plasma Estradiol Levels and Estrogen-Responsive Gene Expression in Estrogen Receptor–Positive Breast Cancer in Postmenopausal Women

2010 ◽  
Vol 28 (7) ◽  
pp. 1161-1167 ◽  
Author(s):  
Anita K. Dunbier ◽  
Helen Anderson ◽  
Zara Ghazoui ◽  
Elizabeth J. Folkerd ◽  
Roger A'Hern ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Estrogen Receptor ◽  
Postmenopausal Women ◽  
Multivariable Analysis ◽  
Independent Set ◽  
Breast Cancers ◽  
Plasma Estradiol ◽  
Er Positive ◽  
Positive Breast Cancer

Purpose To determine whether plasma estradiol (E2) levels are related to gene expression in estrogen receptor (ER)–positive breast cancers in postmenopausal women. Materials and Methods Genome-wide RNA profiles were obtained from pretreatment core-cut tumor biopsies from 104 postmenopausal patients with primary ER-positive breast cancer treated with neoadjuvant anastrozole. Pretreatment plasma E2 levels were determined by highly sensitive radioimmunoassay. Genes were identified for which expression was correlated with pretreatment plasma E2 levels. Validation was performed in an independent set of 73 ER-positive breast cancers. Results The expression of many known estrogen-responsive genes and gene sets was highly significantly associated with plasma E2 levels (eg, TFF1/pS2, GREB1, PDZK1 and PGR; P < .005). Plasma E2 explained 27% of the average expression of these four average estrogen-responsive genes (ie, AvERG; r = 0.51; P < .0001), and a standardized mean of plasma E2 levels and ER transcript levels explained 37% (r, 0.61). These observations were validated in an independent set of 73 ER-positive tumors. Exploratory analysis suggested that addition of the nuclear coregulators in a multivariable analysis with ER and E2 levels might additionally improve the relationship with the AvERG. Plasma E2 and the standardized mean of E2 and ER were both significantly correlated with 2-week Ki67, a surrogate marker of clinical outcome (r = −0.179; P = .05; and r = −0.389; P = .0005, respectively). Conclusion Plasma E2 levels are significantly associated with gene expression of ER-positive breast cancers and should be considered in future genomic studies of ER-positive breast cancer. The AvERG is a new experimental tool for the study of putative estrogenic stimuli of breast cancer.

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