Action Of Tamoxifen Research Articles

Aloe-Emodin Enhances Tamoxifen Cytotoxicity by Suppressing Ras/ERK and PI3K/mTOR in Breast Cancer Cells

Aloe-emodin (AE) is derived from Aloe vera and rhubarb (Rheum palmatum) and exhibits anticancer activities via multiple regulatory mechanisms in various cancers. AE can also enhance the anticancer efficacy of cisplatin, doxorubicin, docetaxel, and 5-fluorouracil; however, its effects remain poorly characterized. MCF-7, MDA-MB-231, MDA-MB-468, BT-474, and HCC-1954 breast cancer cell lines were treated with the indicated conditions of AE, and cell viability assays were performed. The expression levels of signaling proteins were determined by western blot analysis, intracellular reactive oxygen species (ROS), cell cycle distributions, and rates of apoptosis as estimated by flow cytometry. In comparison with other cells, MCF-7 cells were more sensitive to AE treatment; AE enhanced the cytotoxicity of 9[Formula: see text][Formula: see text]g/ml tamoxifen by reducing EGFR, ER[Formula: see text], Ras, ERK, c-Myc, and mTOR protein expression and blocking PI3K and mTOR activation. Finally, although co-treatment of AE with tamoxifen increased intracellular ROS, there were no effects on cell cycle progression. Besides facilitating tamoxifen-induced cell death, AE also enhanced the antiproliferative activity of tamoxifen by blocking Ras/ERK and PI3K/mTOR pathways in breast cancer cells, thus demonstrating the chemosensitizing potential of AE.

Pharmacogenetic testing of allelic variants of the CYP2D6 gene in hormone positive breast cancer

Tamoxifen is the drug of choice for endocrine therapy of hormone receptor- positive breast cancer in women in the reproductive period. The metabolic activity of tamoxifen is determined by the activity of the enzyme CYP2D6, encoded by the gene of the same name: under the action of the enzyme, tamoxifen passes into the metabolically active form, endoxyphene. Pharmacogenetic testing of the CYP2D6 gene in patients with hormone-positive breast cancer can help predict the effectiveness of therapy and assess the risk of side effects with the aim of improving long-term treatment outcomes.

CYP2D6-GENOTYPING IN THE ASSESSMENT OF THE EFFECTIVENESS OF THERAPY WITH TAMOXIFEN IN PATIENTS WITH ADVANCED HORMONE RECEPTOR-POSITIVE BREAST CANCER

Tamoxifen is a drug of choice for endocrine therapy of hormone receptor- positive breast cancer in women of reproductive age. The metabolic activity of tamoxifen is determined by the activity of the CYP2D6 enzyme encoded by the CYP2D6 gene: under the action of the enzyme, tamoxifen converts into the metabolically active form called endoxifen. Pharmacogenetic testing of the CYP2D6 gene in patients with hormone-positive breast cancer can help to predict response to therapy and assess the risk of side effects with the aim of improving long-term treatment outcomes.

Synthesis and Biological Evaluations of Ring Substituted Tetrahydroisoquinolines (THIQs) as Anti-Breast Cancer Agents.

Breast cancer is a leading cause of mortality among women, resulting in more than half a million deaths worldwide every year. Although chemotherapeutic drugs remain the main stay of cancer treatment, it is observed that toxicity to normal cells poses a limitation to their therapeutic values. Moreover, the patient recovery rate from advanced breast cancer by chemotherapy is still unacceptably low. Tetrahydroisoqinoline derivatives (THIQs) were reported to act as selective subtype estrogen receptor antagonists/agonists and may serve as potential therapeutic agents for breast cancer. In continuation of previous work we systematically synthesized and characterized the tetrahydroisoquinoline (THIQs) analogs. In-vitro antiproliferative activity of new substituted tetrahydroisoquinoline analogs were evaluated against human ER (+) MCF-7 (breast), ER (−) MDA-MB-231 (breast) and Ishikawa (endometrial) cancer cell lines using the CellTiter-Glo luminescent cell viability assay. The most active compounds obtained in this study were 2b, 2i, and 3 g as demonstrated by their activity (IC50=0.2 μg/mL, 0.08 μg/mL; 0.61 μg/mL, 0.09 μg/mL; 0.25 μg/mL, 0.11 μg/mL) against MCF-7 and Ishikawa cell lines respectively, in comparison to Tamoxifen activity (IC50=3.99 μg/mL, 7.87 μg/ml). The newly synthesized molecules were docked in the active sites of the ER-α (PDB: 3ERT), ER-β (PDB: 1QKN) and alpha-beta tubulin taxol complex (1JFF) crystal structures to determine the probable binding modes (bioactive conformations) of the active compounds.

Role of Cytochrome P450 Polymorphisms on Breast Cancer Treatment

Pharmacogenetics is one of the key factors that is responsible for biological signaling variations that can lead to various diseases. Being led by genetic mutations, breast cancer is affected at higher level due to pharmacogenetic variations. Chemotherapeutic drug is mainly bio transformed in the liver by cytochrome P450 (CYP) enzyme. CY450 isoforms and polymorphisms direct inter individual and interethnic variability in pharmacokinetics and pharmacodynamics of drugs. This further leads to alteration in cancer prognosis. This paper discusses clinically used drugs in breast cancer treatment where interethnic differences in drug safety and efficacy are known to exist. Best known anticancer drug for estrogen receptor-positive breast cancer is Tamoxifen and its efficacy depends predominantly on genetic variants of CYP2D6. Other polymorphisms of CYP3A4, CYP3A5, and sulfotransferase1A1 (SULT1A1) also provide important information about mechanism of tamoxifen activity and resistance. Many chemotherapeutics like anthracyclines have also showed association with polymorphism of genes (CBR3, ABCB1, glutathione-related transporter genes, oxidative stress-related genes) and clinical outcomes. Many chemotherapeutic drug including taxanes, gemcitabine, capecitabine/5-fluorouracil, vinorelbine, methotrexate, and cyclophosphamide are being studies for the association of genetic variations with their bioactivity.

An Antiestrogenic Activity Score for tamoxifen and its metabolites is associated with breast cancer outcome.

Endoxifen concentrations have been associated with breast cancer recurrence in tamoxifen-treated patients. However, tamoxifen itself and other metabolites also show antiestrogenic anti-tumor activity. Therefore, the aim of this study was to develop a comprehensive Antiestrogenic Activity Score (AAS), which accounts for concentration and antiestrogenic activity of tamoxifen and three metabolites. An association between the AAS and recurrence-free survival was investigated and compared to a previously published threshold for endoxifen concentrations of 5.97ng/mL. The antiestrogenic activities of tamoxifen, (Z)-endoxifen, (Z)-4-hydroxytamoxifen, and N-desmethyltamoxifen were determined in a cell proliferation assay. The AAS was determined by calculating the sum of each metabolite concentration multiplied by an IC50 ratio, relative to tamoxifen. The AAS was calculated for 1370 patients with estrogen receptor alpha (ERα)-positive breast cancer. An association between AAS and recurrence was investigated using Cox regression and compared with the 5.97ng/mL endoxifen threshold using concordance indices. An AAS thresholdof 1798 was associated with recurrence-free survival, hazard ratio (HR) 0.67 (95% confidence interval (CI) 0.47-0.96), bias corrected after bootstrap HR 0.69 (95% CI 0.48-0.99). The concordance indices for AAS and endoxifen did not significantly differ; however, using the AAS threshold instead of endoxifen led to different dose recommendations for 5.2% of the patients. Endoxifen concentrations can serve as a proxy for the antiestrogenic effect of tamoxifen and metabolites. However, for the aggregate effect of tamoxifen and three metabolites, defined by an integrative algorithm, a trend towards improving treatment is seen and moreover, is significantly associated with breast cancer recurrence.

Tamoxifen Suppresses the Growth of Malignant Pleural Mesothelioma Cells.

Malignant pleural mesothelioma (MPM) is a rare but highly aggressive malignancy most often associated with exposure to asbestos. Recent evidence points to oestrogen receptor (ER)-β having a tumour-suppressor role in MPM progression, and this raises the question of whether selective modulators of ERs could play a role in augmenting MPM therapy. We investigated the action of tamoxifen in inhibiting the growth and modulating the cisplatin sensitivity of four MPM cell lines. Tamoxifen inhibited the growth of MPM cells and also modulated their sensitivity to cisplatin. The MPM cell lines expressed ERβ, but the actions of tamoxifen were not blocked by antagonism of nuclear ERs. Tamoxifen treatment repressed the expression of cyclins by MPM cells, resulting in cell-cycle arrest and caspase-3-coupled apoptosis signaling. The ER-independent actions of tamoxifen on MPM cell proliferation and cell-cycle progression may have clinical benefits for a subset of patients with MPM.

Minireview: The Link Between ERα Corepressors and Histone Deacetylases in Tamoxifen Resistance in Breast Cancer.

Approximately 70% of breast cancers express the estrogen receptor (ER)α and are treated with the ERα antagonist, tamoxifen. However, resistance to tamoxifen frequently develops in advanced breast cancer, in part due to a down-regulation of ERα corepressors. Nuclear receptor corepressors function by attenuating hormone responses and have been shown to potentiate tamoxifen action in various biological systems. Recent genomic data on breast cancers has revealed that genetic and/or genomic events target ERα corepressors in the majority of breast tumors, suggesting that the loss of nuclear receptor corepressor activity may represent an important mechanism that contributes to intrinsic and acquired tamoxifen resistance. Here, the biological functions of ERα corepressors are critically reviewed to elucidate their role in modifying endocrine sensitivity in breast cancer. We highlight a mechanism of gene repression common to corepressors previously shown to enhance the antitumorigenic effects of tamoxifen, which involves the recruitment of histone deacetylases (HDACs) to DNA. As an indicator of epigenetic disequilibrium, the loss of ERα corepressors may predispose cancer cells to the cytotoxic effects of HDAC inhibitors, a class of drug that has been shown to effectively reverse tamoxifen resistance in numerous studies. HDAC inhibition thus appears as a promising therapeutic approach that deserves to be further explored as an avenue to restore drug sensitivity in corepressor-deficient and tamoxifen-resistant breast cancers.

Abstract 1797: Loss of FoxO1 expression is associated with decreased IGF-1R levels and alters IGFBP-1 induction in tamoxifen-resistant breast cancer cells

Abstract Breast cancer is one of the leading causes of cancer-related deaths in the world. The majority of breast cancers express estrogen receptor alpha (ERα) and tamoxifen, a selective estrogen receptor modulator, is commonly prescribed as adjuvant therapy for ERα-positive breast cancer patients. The development of chemoresistance is a common occurrence in treated patients, however, the molecular mechanisms associated with acquired tamoxifen resistance are not well defined. Previous work from our lab identified a novel mechanism of tamoxifen action that involved the accumulation of extracellular Insulin-like growth factor binding protein-1 (IGFBP-1) and modulates IGF-1-dependent signaling transduction. Tamoxifen-induced IGFBP-1 induction in this model was mediated by G protein-coupled estrogen receptor (GPER)-dependent CREB activation as shown by phosphorylation on serine 133. To determine IGFBP-1 induction is altered during the development of chemoresistance, this mechanism of action was studied in tamoxifen resistant MCF-7 (TamR) cells. Whereas CREB was constitutively phosphorylated in TamR cells, IGFBP-1 levels were not elevated when compared to parental cells and IGFBP-1 was not induced by tamoxifen treatment in TamR cells. These data suggest that another transcription factor(s) are also necessary for the induction of IGFBP-1 in breast cancer cells. FoxO1 is a known regulator of IGFBP-1 transcription and we tested whether FoxO1 contributes to tamoxifen-induced IGFBP-1 transcription. Our results indicate that FoxO1 expression levels were significantly reduced in TamR cells compared with parental cells. Furthermore, FoxO1 knockdown experiments demonstrated this transcription factor mediates tamoxifen-induced IGFBP-1 induction in MCF-7 cells. Consistent with previously published observations, IGF-1R expression was reduced in TamR cells compared to parental MCF-7 cells. To determine if loss of IGF-1R expression in involved in the loss of FoxO1 expression in TamR cells, IGF-1R was exogenously expressed and FoxO1 expression was measured. IGF-1R expression increases FoxO1 levels and partially restores tamoxifen-induced IGFBP-1 induction in TamR cells. These results suggest that FoxO1-mediated IGFBP-1 accumulation is altered during the development of tamoxifen resistance and is associated with decreased IGF-1R expression. Citation Format: Ali Vaziri-Gohar, Kevin D. Houston. Loss of FoxO1 expression is associated with decreased IGF-1R levels and alters IGFBP-1 induction in tamoxifen-resistant breast cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1797.

Berberine enhances the anti‑tumor activity of tamoxifen in drug‑sensitive MCF‑7 and drug‑resistant MCF‑7/TAM cells.

Berberine, an isoquinoline alkaloid, has been previously demonstrated to possess anti‑breast cancer properties. Tamoxifen is widely used in the prevention and treatment of estrogen receptor-positive breast cancer. Thus, the aim of the present study was to assess whether berberine enhanced the anticancer effect of tamoxifen, and the underlying mechanism involved in this combined effect in tamoxifen-sensitive (MCF-7) and tamoxifen-resistant (MCF-7/TAM) cells using MTS, flow cytometry and western blot assays. The results indicated that berberine demonstrated dose‑and time‑dependent anti‑proliferative activity in MCF‑7 and MCF‑7/TAM cells. Furthermore, the combination of berberine and tamoxifen induced cell growth inhibition more effectively than tamoxifen alone. The present study also demonstrated that combinational treatment is more effective in inducing G1phase arrest and activating apoptosis compared tamoxifen alone, which may be due to upregulation of P21 expression and downregulation of the B‑cell CLL/lymphoma2(Bcl‑2)/Bcl‑2 associated Xprotein ratio. The results of the present study suggested that berberine may potentially be useful as an adjuvant agent in cancer chemotherapy to enhance the effect of tamoxifen, which will be useful for anti‑tumor therapy and further research.

The anti-estrogenic activity of indole-3-carbinol in neonatal rat osteoblasts is associated with the estrogen receptor antagonist 2-hydroxyestradiol.

To gain new insight into the roles of cruciferous vegetable-derived bioactive phytochemicals in bone cells, we investigated the effects of indole-3-carbinol (I3C) on cell proliferation and differentiation in estradiol (E2)-exposed calvarial osteoblasts that were obtained from neonatal rats. Osteoblast activity was assessed by analyzing cellular DNA, cell-associated osteocalcin (OC) levels and alkaline phosphatase (AP) activity. We also examined [(3)H]-estrone (E1) metabolism and estrogen-agonistic and estrogen-antagonistic activities of 2-hydroxy (OH) E1 and 2-OHE2 and their capacity to displace [(3)H]-E2 at ER binding sites using competition studies. I3C did not affect on cellular DNA, OC levels or AP activity. However, I3C completely inhibited E2-induced increases in cell proliferation and differentiation in neonatal rat osteoblasts. Metabolic studies demonstrated that I3C promoted the conversion of [(3)H]-E1 to 2-OHE1 and 2-OHE2 and those higher rates of conversion (twofold-threefold) were archived when a higher dose of I3C was applied. Proliferation and differentiation studies showed that 2-OHE2 but not 2-OHE1 inhibited E2-induced increases in cell proliferation and differentiation via an ER-mediated mechanism. Likewise, Esr1 was expressed at high level than Esr2. 2-OHE1 showed no activity or affinity for ER. This study is the first to show that a bioactive compound derived from cruciferous vegetables, I3C, abolishes the E2-mediated stimulation of cell activities including, proliferation and differentiation, in rat osteoblasts and increases the 2-hydroxylation of E1, resulting in the formation of inactive and anti-estrogenic metabolites. These results suggest that in neonatal rat osteoblasts, the anti-estrogenic effect of I3C is mediated by 2-OHE2 through ER-α.

Autonomous interconversion between adult pancreatic α-cells and β-cells after differential metabolic challenges.

BackgroundEvidence hints at the ability of β-cells to emerge from non-β-cells upon genetic or pharmacological interventions. However, their quantitative contributions to the process of autonomous β-cell regeneration without genetic or pharmacological manipulations remain to be determined.Methods & resultsUsing PANIC-ATTAC mice, a model of titratable, acute β-cell apoptosis capable of autonomous, and effective islet mass regeneration, we demonstrate that an extended washout of residual tamoxifen activity is crucial for β-cell lineage tracing studies using the tamoxifen-inducible Cre/loxP systems. We further establish a doxycycline-inducible system to label different cell types in the mouse pancreas and pursued a highly quantitative assessment to trace adult β-cells after various metabolic challenges. Beyond proliferation of pre-existing β-cells, non-β-cells contribute significantly to the post-challenge regenerated β-cell pool. α-cell trans-differentiation is the predominant mechanism upon post-apoptosis regeneration and multiparity. No contributions from exocrine acinar cells were observed. During diet-induced obesity, about 25% of α-cells arise de novo from β-cells. Ectopic expression of Nkx6.1 promotes α-to-β conversion and insulin production.ConclusionsWe identify the origins and fates of adult β-cells upon post-challenge upon autonomous regeneration of islet mass and establish the quantitative contributions of the different cell types using a lineage tracing system with high temporal resolution.

Oestrogenic action of neonatal tamoxifen on the hypothalamus and reproductive system in female mice.

Tamoxifen, a selective oestrogen receptor modulator, is widely used for both the treatment and prevention of breast cancer in women; however, it is known to have adverse effects in the female reproductive system. Growing evidence suggests that oestrogen-sensitive neuron populations of the anteroventral periventricular (AVPV) nucleus and arcuate (ARC) nucleus, especially kisspeptin neurons, play a pivotal role in the timing of puberty onset and reproductive function. The aim of the present study was to evaluate whether neonatal exposure to tamoxifen affects oestrogenic actions in the brain and reproductive function in mice. On 1 to 5 postnatal days, female pups were injected subcutaneously with sesame oil (sham), oestradiol benzoate (EB; 20 µg kg-1), tamoxifen (0.4 mg kg-1) or EB+tamoxifen. Control mice received no treatment. Mice in the EB, tamoxifen and tamoxifen+EB groups exhibited advanced vaginal opening, disrupted oestrous cycles and a decreased follicular pool. Conversely, in these groups, there was a reduction in kisspeptin (Kiss1) mRNA expression, the neuronal density of AVPV and ARC nuclei and LH and oestradiol concentrations in the serum. The results of the present study confirm oestrogenic actions of tamoxifen in the brain and reproductive system. In addition, we show, for the first time, that tamoxifen has oestrogenic effects on the oestrogen-sensitive hypothalamic AVPV and ARC nuclei controlling the reproductive axis in female mice.

Could Caffeic Acid Phenethyl Ester Expand the Antitumor Effect of Tamoxifen in Breast Carcinoma?

ABSTRACTDespite tamoxifen (TAM) is beneficial in treating a significant proportion of patients with breast cancer, many women still relapse after long-term therapy. Caffeic acid phenethyl ester (CAPE) is a component of honeybee propolis, with a plethora of important biological actions including anticancer activity. This study aimed to explore the cytotoxicity, the type of drugs interaction as well as the apoptotic and autophagic pathways of the combined treatment of TAM and CAPE in MCF-7 cells. Their antitumor activity and effect on survival of mice bearing Ehrlich tumor were also analyzed. The results showed synergistic cytotoxic effects, manifested by significant activation of apoptotic machinery, along with downregulation of protein levels of Bcl-2 and beclin-1, upon using the combination regimen. However, the ratio between microtubule-associated protein light chain 3-II and -I was not altered. Moreover, a decrease in vascular endothelial growth factor level was detected. Similarly, TAM + CAPE increased the life span of tumor-bearing animals and caused a marked regression in their tumor size and weight compared with those treated with either TAM or CAPE alone. In conclusion, CAPE relatively improved the anticancer activity of TAM in both in vitro and in vivo models via its apoptotic and angiostatic potentials.

Abstract P1-16-07: Pharmacogenomics-pharmacokinetics study of selective estrogen-receptor modulators with intra-patient dose-escalation for Japanese breast cancer patients

Abstract Background The association between CYP2D6 polymorphisms and efficacy of tamoxifen (TAM) is inconclusive, partly due to inaccurate prediction of active metabolite, endoxifen exposure by solely CYP2D6 genotype. Moreover, TAM dose escalation is not effective for poor metabolizers. Since the contribution of CYP2D6 to toremifen (TOR) activation is small, TOR might be a good alternative to TAM for poor metabolizers. Methods Patients who maintained good compliance with TAM or TOR without regular use of strong CYP2D6 inhibitors were enrolled in a screening study. The pharmacokinetics (PK) of TAM or TOR and the pharmacogenomics (PGx) of metabolizing enzymes and transporters were assessed. Associations between TAM and TOR PK and PGx, other CYP inhibitor use, and smoking status were examined by regression analysis. An intra-patient dose escalation study was conducted for patients showing low endoxifen levels during TAM treatment (n = 14). TAM was switched to 40 mg of TOR, and then increased to 120 mg for ≥24 weeks with periodic PK sampling. Total TAM or TOR activity was calculated as the sum of the concentration of each active metabolite adjusted by their respective in vitro activity. Results CYP2D6 genotype was the major determinant for TAM activity (p < 0.01) for Japanese breast cancer patients. Current smoking status (p = 0.07) and CYP2C19 (p = 0.07), but not CYP2D6 genotype (p = 0.61), showed marginally significant effects on TOR activity. TOR activity sufficiently increased with dose escalation from 40 mg to 120 mg, even among the poor TAM metabolizers, and was maintained for ≥24 weeks. Total Activity of TOR (ng/mL) Screening (n=271)Intra-patient dose escalation (n=14)Dose (mg)4040120120*120/40120*/40120*/120Mean (ng/mL)4168.53218.18758.67268.03.12.60.9Median (ng/mL)3865.43020.38924.67579.72.82.50.8SD1446.21207.01707.11793.21.20.80.2p-value0.04 <0.01<0.010.054*(Sample taken at ≥24 weeks) Conclusion Since the contribution of CYP2D6 to TOR metabolism is relatively small, TOR is a valid alternative to TAM, especially in patients predicted to be poor TAM metabolizers. Further clinical trials are warranted to validate this concept. Citation Format: Ohno S, Ishiguro H, Yamamoto Y, Takao S, Sato N, Fujisawa T, Kadoya T, Kuroi K, Bando H, Teramura Y, Iwata H, Tanaka S, Toi M. Pharmacogenomics-pharmacokinetics study of selective estrogen-receptor modulators with intra-patient dose-escalation for Japanese breast cancer patients. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-16-07.

Abstract P3-07-46: CYPTAM-BRUT 3: Endometrial thickness cannot be used as a marker for tamoxifen metabolization in postmenopausal breast cancer patients

Abstract Background: Tamoxifen is commonly used for the treatment of all stages of estrogen receptor (ER) positive breast cancer (BC), the largest group of BC. In postmenopausal women, known endometrial side-effects are cystic appearance, hyperplasia, polyps and endometrial cancer. Tamoxifen is converted through several CYP450 enzymes into the active metabolite endoxifen. Patients with particular single nucleotide polymorphisms (SNPs) in those CYP450 enzymes (e.g. CYP2D6) have lower endoxifen concentrations and therefore could experience less benefit from tamoxifen. However, the clinical significance stays controversial in the literature as results remain contradictory. Our primary hypothesis is that women with lower endoxifen levels do not have the typical tamoxifen-induced increase in endometrial thickness. The aim of this study is to test the association between endoxifen concentration and the increase in double endometrial thickness (DET). Patients and methods: CYPTAM-BRUT 3 is a prospective, multicentric study including postmenopausal women with an ER positive BC receiving tamoxifen in the adjuvant setting. Primary objective is the association between serum endoxifen levels and change in DET between baseline and follow-up after 3 - 6 months. Secondary objectives are investigating the relation between serum endoxifen levels and other endometrial changes (i.e. the presence of cysts/polyps), menopausal symptoms assessed with a questionnaire and serum levels of follicle-stimulating hormone (FSH) and sex hormone-binding globulin (SHBG). Other objectives are the association between the 'CYP2D6 tamoxifen activity score', based on SNPs and co-medication, and DET, other endometrial changes, FSH and SHBG. The CYPTAM-BRUT 3 study is a sub-study of the CYPTAM study in Leiden, The Netherlands, with survival as primary outcome. Results: 144 women were included in 19 hospitals. There was no significant association found between endoxifen and change in DET (p=0.888), as for the association between endoxifen and the development of cysts or polyps (p=0.208). For the questionnaire items no correlation was found (p≥0.051). Changes of FSH and SHBG were in the range of what would be expected during tamoxifen treatment in the general population and there was no association with endoxifen (p=0.726 and p=0.181). In addition, no association was found between the CYP2D6 TAS score and DET (p=0.613), other endometrial changes (p=0.196), FSH (p=0.976) and SHBG (p=0.900). Conclusion: Our study is one of the first studies that prospectively investigated the relation between tamoxifen metabolization, in correlation with endometrial thickness and SNPs. We can conclude that the typical increase in endometrial thickness seen in a significant proportion of postmenopausal women under tamoxifen cannot be used to predict that those women have a high endoxifen concentration or that women without an increased endometrial thickness have a significantly lower endoxifen concentration. The same conclusions can be made for the other tamoxifen-induced changes as cysts and polyps, menopausal symptoms, FSH and SHBG. It may also apply to tamoxifen efficacy but further prospective studies looking at survival are needed to answer that question. Citation Format: Poppe A, Dieudonné A-S, Lintermans A, Laenen A, Blomme C, Lambrechts D, Wildiers H, Christiaens M-R, Timmerman D, Van Calster B, Vereecke C, Vandeputte G, Fontaine C, Decloedt J, Berteloot P, Depypere H, Joerger M, Dezentjé V, Neven P. CYPTAM-BRUT 3: Endometrial thickness cannot be used as a marker for tamoxifen metabolization in postmenopausal breast cancer patients. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-07-46.

Efficacy of tamoxifen and miltefosine combined therapy for cutaneous leishmaniasis in the murine model of infection with Leishmania amazonensis.

The objective of this study was to characterize in vitro interactions and evaluate the antileishmanial activity of tamoxifen and miltefosine combinations. Interactions between drugs were evaluated in vitro against Leishmania amazonensis promastigotes and intracellular amastigotes by a modified isobologram method. Four different drug ratios were used to calculate the FIC index (FICI) and the mean sum of FICI. Treatment of L. amazonensis-infected BALB/c mice was initiated 4 weeks post-infection. Mice were treated with the half-maximal effective dose (ED50) or half the ED50 of tamoxifen and miltefosine orally for 15 days. Efficacy was evaluated by lesion growth and parasite burden measured through luciferase detection at the end of treatment and 30 days later. Characterization of growth curves and stepwise increase in drug concentrations in vitro were used to measure survival and resistance selection of parasite populations submitted to combination treatment. No in vitro interactions between tamoxifen and miltefosine were found. In infected mice, the combination of tamoxifen and miltefosine at doses corresponding to half the ED50 was more effective than monotherapy with either tamoxifen or miltefosine. When the ED50 was employed, the efficacy of the combination was equivalent to miltefosine monotherapy. In vitro, tamoxifen was able to retard or suppress the growth of parasites treated with miltefosine. In vitro and in vivo studies revealed no interaction between tamoxifen and miltefosine. Tamoxifen was able to hinder the emergence of miltefosine resistance.

Mechanism of Action and Potential Use of Tamoxifen in the Treatment of Acute Mania

Mechanism of Action and Potential Use of Tamoxifen in the Treatment of Acute Mania

Tamoxifen Action in ER-Negative Breast Cancer.

Breast cancer is a highly heterogeneous disease. Tamoxifen is a selective estrogen receptor (ER) modulator and is mainly indicated for the treatment of breast cancer in postmenopausal women and postsurgery neoadjuvant therapy in ER-positive breast cancers. Interestingly, 5–10% of the ER-negative breast cancers have also shown sensitivity to tamoxifen treatment. The involvement of molecular markers and/or signaling pathways independent of ER signaling has been implicated in tamoxifen sensitivity in the ER-negative subgroup. Studies reveal that variation in the expression of estrogen-related receptor alpha, ER subtype beta, tumor microenvironment, and epigenetics affects tamoxifen sensitivity. This review discusses the background of the research on the action of tamoxifen that may inspire future studies to explore effective therapeutic strategies for the treatment of ER-negative and triple-negative breast cancers, the latter being an aggressive disease with worse clinical outcome.

Alcohol Regulates Genes that Are Associated with Response to Endocrine Therapy and Attenuates the Actions of Tamoxifen in Breast Cancer Cells.

Hereditary, hormonal, and behavioral factors contribute to the development of breast cancer. Alcohol consumption is a modifiable behavior that is linked to increased breast cancer risks and is associated with the development of hormone-dependent breast cancers as well as disease progression and recurrence following endocrine treatment. In this study we examined the molecular mechanisms of action of alcohol by applying molecular, genetic, and genomic approaches in characterizing its effects on estrogen receptor (ER)-positive breast cancer cells. Treatments with alcohol promoted cell proliferation, increased growth factor signaling, and up-regulated the transcription of the ER target gene GREB1 but not the canonical target TFF1/pS2. Microarray analysis following alcohol treatment identified a large number of alcohol-responsive genes, including those which function in apoptotic and cell proliferation pathways. Furthermore, expression profiles of the responsive gene sets in tumors were strongly associated with clinical outcomes in patients who received endocrine therapy. Correspondingly, alcohol treatment attenuated the anti-proliferative effects of the endocrine therapeutic drug tamoxifen in ER-positive breast cancer cells. To determine the contribution and functions of responsive genes, their differential expression in tumors were assessed between outcome groups. The proto-oncogene BRAF was identified as a novel alcohol- and estrogen-induced gene that showed higher expression in patients with poor outcomes. Knock-down of BRAF, moreover, prevented the proliferation of breast cancer cells. These findings not only highlight the mechanistic basis of the effects of alcohol on breast cancer cells and increased risks for disease incidents and recurrence, but may facilitate the discovery and characterization of novel oncogenic pathways and markers in breast cancer research and therapeutics.