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The risk factors for and risk assessment of breast cancer, recommendations for risk reduction, and roles of tamoxifen and raloxifene in the prevention of breast cancer are discussed.
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Expression of estrogen and progesterone hormone receptors indicates a favorable prognosis due to the successful use of hormonal therapies such as tamoxifen and aromatase inhibitors. Unfortunately, 15-20% of patients will experience breast cancer recurrence despite continued use of tamoxifen. Drug resistance to hormonal therapies is of great clinical concern so it is imperative to identify novel molecular factors that contribute to tumorigenesis in hormone receptor positive cancers and/or mediate drug sensitivity. The hope is that targeted therapies, in combination with hormonal therapies, will improve survival and prevent recurrence. We have previously shown that the DEK oncogene, which is a chromatin remodeling protein, supports breast cancer cell proliferation, invasion and the maintenance of the breast cancer stem cell population. In this report, we demonstrate that DEK expression is associated with positive hormone receptor status in primary breast cancers and is up-regulated in vitro following exposure to the hormones estrogen, progesterone, and androgen. Chromatin immunoprecipitation experiments identify DEK as a novel estrogen receptor α (ERα) target gene whose expression promotes estrogen-induced proliferation. Finally, we report for the first time that DEK depletion enhances tamoxifen-induced cell death in ER+ breast cancer cell lines. Together, our data suggest that DEK promotes the pathogenesis of ER+ breast cancer and that the targeted inhibition of DEK may enhance the efficacy of conventional hormone therapies.
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The records of 41,726 patients with breast cancer (28,266 received TMX and 13,460 did not) were obtained from the Taiwan National Health Insurance Research Database for the period from January 2000 to December 2008. Three-fold women without breast cancer were the control group (N = 125, 178). The main end point was developing hyperlipidemia during the follow-up.
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Mitochondrial reactive oxygen species (ROS) and endothelial dysfunction are key contributors to cerebrovascular pathophysiology. We previously found that 17beta-estradiol profoundly affects mitochondrial function in cerebral blood vessels, enhancing efficiency of energy production and suppressing mitochondrial oxidative stress. To determine whether estrogen specifically affects endothelial mitochondria through receptor mechanisms, we used cultured human brain microvascular endothelial cells (HBMECs). 17beta-Estradiol treatment for 24 h increased mitochondrial cytochrome c protein and mRNA; use of silencing RNA for estrogen receptors (ERs) showed that this effect involved ERalpha, but not ERbeta. Mitochondrial ROS were determined by measuring the activity of aconitase, an enzyme with an iron-sulfur center inactivated by mitochondrial superoxide. 17beta-Estradiol increased mitochondrial aconitase activity in HBMECs, indicating a reduction in ROS. Direct measurement of mitochondrial superoxide with MitoSOX Red showed that 17beta-estradiol, but not 17alpha-estradiol, significantly decreased mitochondrial superoxide production, an effect blocked by the ER antagonist, ICI-182,780 (fulvestrant). Selective ER agonists demonstrated that the decrease in mitochondrial superoxide was mediated by ERalpha, not ERbeta. The selective estrogen receptor modulators, raloxifene and 4-hydroxy-tamoxifen, differentially affected mitochondrial superoxide production, with raloxifene acting as an agonist but 4-hydroxy-tamoxifen acting as an estrogen antagonist. Changes in superoxide by 17beta-estradiol could not be explained by changes in manganese superoxide dismutase. Instead, ERalpha-mediated decreases in mitochondrial ROS may depend on the concomitant increase in mitochondrial cytochrome c, previously shown to act as an antioxidant. Mitochondrial protective effects of estrogen in cerebral endothelium may contribute to sex differences in the occurrence of stroke and other age-related neurodegenerative diseases.
Individuals with familial adenomatous polyposis (FAP) harbor a germline mutation in adenomatous polyposis coli (APC). The major clinical manifestation is development of multiple colonic tumors at a young age due to stochastic loss of the remaining APC allele. Extracolonic features, including periampullary tumors, gastric abnormalities, and congenital hypertrophy of the retinal pigment epithelium, may occur. The objective of this study was to develop a mouse model that simulates these features of FAP. We combined our Lrig1-CreERT2/+ mice with Apcfl/+ mice, eliminated one copy of Apc in leucine-rich repeats and immunoglobulin-like domains protein 1 (Lrig1)-positive (Lrig1(+)) progenitor cells with tamoxifen injection, and monitored tumor formation in the colon by colonoscopy and PET. Initial loss of one Apc allele in Lrig1(+) cells results in a predictable pattern of preneoplastic changes, culminating in multiple distal colonic tumors within 50 days of induction, as well as the extracolonic manifestations of FAP mentioned above. We show that tumor formation can be monitored by noninvasive PET imaging. This inducible stem cell-driven model recapitulates features of FAP and offers a tractable platform on which therapeutic interventions can be monitored over time by colonoscopy and noninvasive imaging.
Prophylactic and symptomatic RT is widely used in the German-speaking countries, but patient numbers are small. The clinical results indicate that RT is a highly effective and well-tolerated treatment.
The increased interest in phytoestrogens in the management of menopausal symptoms followed the publication of the Women's Health Initiative study. A wide-spread perception that these plant-derived compounds are equivalent to estrogen was established. These compounds evolved to fulfill the needs of plant physiological processes and are natural for the plant cells but not natural to the human cell. Epidemiological data suggest a possible protective effect of phytoestrogen if consumed during adolescence, but later on in life this effect is not clear. The utility of phytoestrogen as a "natural and safe" alternative to estrogen in alleviating vasomotor symptoms has failed the test in randomized clinical trials. Because many breast cancer sufferers seek in phytoestrogen a relief of estrogen deficiency symptoms, the possible interaction of such remedies with risk of recurrence of breast cancer or interference with tamoxifen action should not be overlooked.
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Premenopausal women, and postmenopausal women without a previous significant history of hot flashes, appear to have less trouble with tamoxifen-associated hot flashes, compared with postmenopausal women with a previous history of moderate or worse hot flashes.
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Hip and other fractures were common in an older population-based cohort of breast cancer survivors, and aromatase inhibitor use was associated with an increase in the short-term risk of hip fractures not detected in randomized controlled trials.
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A randomised-controlled trial of postmenopausal women who had taken at least one year of adjuvant tamoxifen therapy.
Therefore, based on the potent antioxidant and anticancer activity of leaves extracts, it appears that S. crispus grown in the North-east of Malaysia (Kelantan) is a potential source of anticarcinogenic therapeutic compounds.
Targeted deletion of MLCK in adult mouse smooth muscle resulted in severe gut dysmotility characterized by weak peristalsis, dilation of the digestive tract, and reduction of feces excretion and food intake. There was also abnormal urinary bladder function and lower blood pressure. Isolated muscles showed a loss of RLC phosphorylation and force development induced by K(+)-depolarization. The kinase knockout also markedly reduced RLC phosphorylation and force development with acetylcholine which activates Ca(2+)-sensitizing signaling pathways.
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A randomized, double-blind study was conducted with 40 premenopausal women aged 18-40 years who had been diagnosed with fibroadenoma of the breast. The patients were divided into two groups: Group A (placebo, n = 20), and Group B (raloxifene 60 mg, n = 20).The medication was taken for 22 days initiating from the first day of the menstrual cycle. An excisional biopsy was performed on the 23rd day. At the time of biopsy, a sample of normal breast tissue was collected to evaluate protein expression of Ki-67 and Bcl-2. The Student's t test and Chi-square test were used for statistical data analysis and the significance level was established at 5%.
A third of breast cancers (BC) occur in women ≥65 years (seniors). Anti-estrogen therapy (AET) significantly reduces BC recurrence and death. This study characterizes determinants of adherence to AET in seniors with BC. Provincial cancer registry and administrative claims data were accessed for all non-metastatic BC diagnosed in Quebec (1998-2005) to identify seniors treated for 5 years with AET. Multivariate linear regression was used to assess the association with patient, disease, and physician characteristics and the 5-year medication possession ratio (MPR) for each patient. 4,715 women were included (mean age: 72.9). Mean MPR was 83.5%, 79% of patients reached a 5-year MPR of ≥80%, and 34% discontinued AET at some point during treatment. The cumulative probability of discontinuation was 33.8% (mean time to discontinuation 2.3 years). The MPR decreased with increasing age and non-BC related hospitalizations, p < 0.05. Each new medication added during the 5-years decreased the MPR by 0.3% (p < 0.05). Women with in situ disease, on antidepressants at baseline, or treated with Tamoxifen had a lower MPR by 6.5% (p = 0.0002), 4.7% (p = 0.003) and 6% (p = 0.001), respectively. Switching AET type was associated with a lower MPR by 5.3% (p = 0.002) if the switch occurred during the first year. Optimal 5-year adherence to AET in seniors with BC remained a challenge and medication discontinuation rates were high. Advanced age, increasing number of hospitalizations, in situ disease, baseline use of antidepressants, Tamoxifen (versus aromatase inhibitors), early switches of AET type, and newly added medications significantly reduced the MPR.
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Ferrociphenols (FCs) and their oxidized, electrophilic quinone methide metabolites (FC-QMs) are organometallic compounds related to tamoxifen that exhibit strong antiproliferative properties. To evaluate the reactivity of FC-QMs toward cellular nucleophiles, we studied their reaction with selected thiols. A series of new compounds resulting from the addition of these nucleophiles, the FC-SR adducts, were thus synthesized and completely characterized. Such conjugates are formed upon metabolism of FCs by liver microsomes in the presence of NADPH and thiols. Some of the FC-SR adducts exhibit antiproliferative properties comparable to those of their FC precursors. Under oxidizing conditions they either revert to their FC-QM precursors or transform into new quinone methides (QMs) containing the SR moiety, FC-SR-QM. These results provide interesting data about the reactivity and mechanism of antiproliferative effects of FCs, and also open the way to a new series of organometallic antitumor compounds.
Treatment with TMX or RLX did not reduce the incidence of scoliosis but decreased the curve magnitudes at 40 weeks. The underlying mechanism associated with the decrease in curve magnitudes may be the early maturation of growth plates, thereby possible deceleration of the growth rate of the vertebral column and increase in bone density. RLX is as effective as TMX in preventing the progression of scoliotic curves in melatonin deficient bipedal mice.
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In the Stockholm trial, breast cancer survivors were randomized to HT (estradiol and progestogen) or to a control group (no treatment). A subgroup of 75 women was studied (38 with HT, 37 controls). Fifty patients were on concomitant tamoxifen. Patients completed three questionnaires (EORTC QLQ C-30, EORTC QLQ-BR 23 and the Hospital Anxiety and Depression Scale (HADS)) during 1 year of treatment.
Between 30% and 50% of American women will endure a clinical fracture during their lifetime due to the loss of bone mineral density that occurs with menopausal estrogen loss. This article is part one in a two-part series on osteoporosis. Part two will appear in the August 2008 issue of ORTHOPEDICS.
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Oral raloxifene administration (60 mg/day) for 3 months lowered serum MDA and NO levels with favorable effects on serum lipid parameters in postmenopausal women, who were undergoing long-term hemodialysis treatment for chronic renal failure.
The recently released results from a pivotal Phase III study in postmenopausal women demonstrated statistically significant improvements of ospemifene 60 mg/day in symptoms of vulvar and vaginal atrophy over the use of non-hormonal vaginal lubricant. Ospemifene also appeared to be well tolerated, with few patients experiencing side effects. The additional positive results on bone and the breast observed in preclinical studies need to be clinically confirmed to extend the therapeutic potential of this new SERM.
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Between Jan 1, 2003, and June 15, 2006, 3104 eligible patients were enrolled and randomly assigned to the two treatment groups (1552 to tamoxifen and 1552 to anastrozole). As of Feb 28, 2015, follow-up information was available for 3083 patients for overall survival and 3077 for all other disease-free endpoints, with median follow-up of 9·0 years (IQR 8·2-10·0). In total, 212 breast cancer-free interval events occurred: 122 in the tamoxifen group and 90 in the anastrozole group (HR 0·73 [95% CI 0·56-0·96], p=0·0234). A significant time-by-treatment interaction (p=0·0410) became evident later in the study. There was also a significant interaction between treatment and age group (p=0·0379), showing that anastrozole is superior only in women younger than 60 years of age. Adverse events did not differ between the groups, except for thrombosis or embolism--a known side-effect of tamoxifen-for which there were 17 grade 4 or worse events in the tamoxifen group versus four in the anastrozole group.
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The effects of ZK 191703 (ZK), a pure antiestrogen, on ovulation, follicle development and peripheral hormone levels were investigated in rats with 4-day estrus cycle and gonadotropin-primed immature rats in comparison to tamoxifen (TAM)-treatment. In adult rats, a single s.c. injection of ZK (5 mg/kg) or TAM (5 mg/kg) at an early stage of the estrus cycle (diestrus 9:00) inhibited ovulation, and was associated with suppression of the surge of preovulatory LH, FSH and progesterone. In rats treated with ZK or TAM at a late stage of the estrus cycle (proestrus 9:00), no inhibitory effects on ovulation, the gonadotropin and progesterone surge were detected. ZK treatment at diestrus 9:00, in contrast to TAM, increased the baseline LH level. When immature rats were treated with antiestrogens in the earlier stage of follicular development, 6 and 30 h but not 48 h or later after injection of gonadotropin (PMSG), ovulation was attenuated, associated with a lowered progesterone level. Unruptured preovulatory follicles were found in most of the ovaries from anovulatory animals treated with ZK or TAM. Antiestrogens, ZK and TAM administered at an early phase of the estrus cycle delay the follicular development functionally and inhibit ovulation in rats and suppression of the preovulatory progesterone surge.
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Tamoxifen has been widely used to treat breast cancer as an endocrine therapy. However, tamoxifen is known to enhance the risk of developing endometrial cancer. We want to examine the effect of tamoxifen on endometrial cancer. In our retrospective study, we found that high grade, high stage, and lymph node metastasis were more common in tamoxifen users. In vitro 4-hydroxytamoxifen (OHT) induced cell proliferation and cell cycle promotion in type I and type II endometrial cancer cell lines, and this proliferation was blocked by GPER silencing. Treatment with OHT increased EGFR and ERK phosphorylation and the mRNA and protein levels of cyclin D1 and GPER. Taken together, our data demonstrate that endometrial cancer patients with tamoxifen treatment exhibit more aggressive histological subtypes and worse prognosis. OHT is a proliferation-inducing agent for endometrial cancer cells, and the GPER/EFGR/ERK/cyclin D1 pathway is involved in this process.
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Evidence of the incidence and risk of osteonecrosis of the jaw (ONJ) in Asian osteoporosis populations receiving different osteoporosis medications is lacking. We found that there is no excess incidence of or risk for ONJ in osteoporosis patients >50 years old using alendronate as compared with patients using raloxifene or calcitonin under real-world conditions in Taiwan.
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This study provides clinical evidence that confirms the basic work that has shown high EGFR can indicate resistance to tamoxifen. It suggests that careful measurement of EGFR protein expression might define a subset of low-stage patients that could benefit from an alternative therapy.
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Tamoxifen is the antihormonal treatment of choice for postmenopausal breast cancer patients with positive estrogen receptors. One of the most significant and deleterious side-effects of TAM treatment appears to be a proliferative effect on the endometrium, including endometrial cancer. Today no active screening for patients treated with tamoxifen other than routine annual gynecologic surveillance is recommended, however many investigators have recommended that those women should warrant closer gynecological surveillance for endometrial cancer during treatment, especially those with high-risk factors. This article evaluates the diagnostic flow chart for the surveillance of endometrial pathologies in tamoxifen-treated breast cancer patients, according to the literature and to the Committee Opinion of the Triveneto Directors of Gynecological and Obstetrical Departments (North-east Italy).
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Estrogen augments breast cancer cell (18)F-FDG uptake by stimulating glycolysis and hexokinase activity via membrane-initiated E(2) action that activates the PI3K-Akt pathway. These findings yield important insight into our understanding of the biology of breast cancer metabolism and may have potential implications for (18)F-FDG uptake as a surrogate marker of therapeutic response.
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Acute pseudo-obstruction of the colon is a disorder characterised by an increase in intra-luminal pressure that leads to ischaemia and necrosis of the intestinal wall. The mechanism that produces the lesion is unknown, although it has been associated with: trauma, anaesthesia, or drugs that alter the autonomic nervous system. The pathophysiology of medication induced colon toxicity can progress to a perforated colon and potentially death.
In this experimental study on endometriosis, the majority of the implants were successfully detected with technetium-(99mTc) labeled red blood cell scintigraphy.
Twenty-six patients received treatment as scheduled. 81% were pre-treated with tamoxifen and 69% had received prior aromatase inhibitors in combination with goserelin. The majority of patients (69%) presented with visceral metastases. Complete response was observed in a single patient, partial response in three and disease stabilisation ≥ 6 months in eleven patients, resulting in a CBR of 58%. Median TTP was 6 months (95%confidence interval (CI), 2.4-9.6) and OS 32 months (95%CI, 14.28-49.72), respectively.