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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Breast cancer is the most common cancer of women worldwide. Its frequency increases throughout the female lifespan. Epidemiological research has clearly identified important reproductive risk factors for breast cancer, including age at menarche, age at menopause, age at first-term pregnancy and nulliparity, which provide important clues to the hormonal origin of this disease. The widespread use of exogenous sex steroids as contraceptive agents and as hormonal replacement therapy has been a source of concern and generates discussion about their effects on breast health. Lifestyle changes, exercise or diet could play a role in primary prevention of breast cancer. Regular exercise, ingestion of adequate amounts of fruit and vegetables, limiting alcohol consumption, avoidance of obesity in post-menopausal women, and perhaps the use of olive oil, may all have a protective effect and should be considered by women. There is insufficient scientific evidence of the role played by phyto-oestrogens on breast cancer risk. Other preventive measures that include the use of drugs such as statins or aspirin should not be recommended until we have more information about their effects on the breast. Especially for high-risk women, all the aforementioned measures may be not enough, and chemo-prevention should be considered. The use of selective oestrogen receptor modulators (SERMs) to reduce breast cancer risk is still being evaluated. Tamoxifen was the first SERM approved for the reduction of breast cancer incidence in women at high risk. However its use has limitations, due to significant side effects. Raloxifene has been approved for the prevention and treatment of post-menopausal osteoporosis and has provided excellent indications of breast cancer risk reduction, with a more favourable profile than tamoxifen.
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PMID:Prophylaxis approach to a-symptomatic post-menopausal women: breast cancer. 1612 55

Breast and ovarian cancers are the second and fifth leading causes of cancer death, respectively, among women in the United States. Individuals with breast cancer have a 20--30% chance of having at least one relative with the disease. However, only 5--10% of the cases are a direct result of germline mutations in highly penetrable genes, such as BRCA1 and BRCA2 (BRCA1/2) as well as genes TP53 and PTEN. Since 1996, genetic testing for these mutations has been clinically available. A strategy for the management of women at increased familial risk of breast and ovarian cancers is described, which includes genetic assessment, chemoprevention, radiologic screening, and clinical and self-examination. Genetic testing should occur within a cancer genetic clinic after genetic counseling. A blood sample allows determination of the presence of the BRCA1 and BRCA2 genes, the TP53 gene, the PTEN gene, and the ATM gene. Tumor examination has identified a growth factor receptor gene, human epidermal growth factor receptor (HER-2). With regard to diet and lifestyle, women at increased risk of breast cancer could be advised to reduce dietary fat, avoid obesity, decrease alcohol consumption, and take regular exercise. Although chemoprotection is a valuable consideration, it is important to emphasize that the use of Tamoxifen in BRCA1 and BRCA2 mutation carriers is not established, nor is the optimum duration of benefit. An overview of the main outcomes of the current published studies confirms a 38% decrease in breast cancer incidence with Tamoxifen but recommends its use be restricted to women at high risk of breast cancer and low risk for potential side effects. The role of bilateral risk-reducing mastectomy or prophylactic mastectomy has been controversial for several reasons, including the psychosocial significance of the breast in Western cultures, the wide acceptance of breast conservation in surgery for early breast cancer, and the previous lack of data on its efficacy. The surgical procedure should aim to remove substantially all at-risk breast tissue. However, there is a balance between reduction of cancer risk and cosmetic outcome. Bilateral prophylactic oophorectomy can significantly decrease ovarian cancer risk in women who carry BCRA1 mutations. Oophorectomy lowers the risk of breast cancer, even in women who have previously used hormone replacement therapy. There are no published randomized controlled trials examining the effectiveness of mammographic screening in women under 50 years of age with a family history of breast cancer. However, the published studies do suggest that mammographic screening of a high-risk group of women under 50 years of age may detect cancer at a rate equivalent to that seen in women 10 years older with normal risk. Other initial studies also support MRI as having a greater sensitivity than mammography in high-risk women. Breast clinical and self-examination is often advocated, but its effectiveness is unproved, and only one randomized study has been undertaken in women at risk. On the basis of this study as well as one nonrandomized study, it can be concluded that clinical examination as well as mammography are essential in detecting breast cancer. under 50 years of age with a family history of breast cancer. However, the published studies do suggest that mammographic screening of a high-risk group of women under 50 years of age may detect cancer at a rate equivalent to that seen in women 10 years older with normal risk. Other initial studies also support MRI as having a greater sensitivity than mammography in high-risk women. Breast clinical and self-examination is often advocated, but its effectiveness is unproved, and only one randomized study has been undertaken in women at risk. On the basis of this study as well as one nonrandomized study, it can be concluded that clinical examination as well as mammography are essential in detecting breast cancer.
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PMID:Breast cancer and ovarian cancer genetics. 1621 1

Body mass index (BMI) is associated with breast cancer risk, but its relationship with stage at diagnosis is unclear. BMI was calculated for patients in the North American Fareston and Tamoxifen Adjuvant trial, and was correlated with clinicopathologic factors, including stage at diagnosis. One thousand eight hundred fourteen patients were enrolled in the North American Fareston and Tamoxifen Adjuvant study; height and weight were recorded in 1451 (80%) of them. The median BMI was 27.1 kg/m2 (range, 14.7-60.7). The median patient age was 68 years (range, 42-100); median tumor size was 1.3 cm (range, 0.1-14 cm). One thousand seven hundred ninety-three (99.0%) patients were estrogen receptor positive, and 1519 (84.7%) were progesterone receptor positive. There was no significant relationship between BMI (as a continuous variable) and nodal status (P = 0.469), tumor size (P = 0.497), American Joint Committee on Cancer stage (P = 0.167), grade (P = 0.675), histologic subtype (P = 0.179), or estrogen receptor status (P = 0.962). Patients with palpable tumors, however, had a lower BMI than those with nonpalpable tumors (median 26.4 kg/m2 vs 27.5 kg/m2, P < 0.001). Similar results were found when BMI was classified as a categorical variable (<25 vs 25-29.9 vs > or =30). Increased BMI does not lead to a worse stage at presentation. Obese patients, however, tend to have nonpalpable tumors. Mammography in this population is especially important.
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PMID:Body mass index influences palpability but not stage of breast cancer at diagnosis. 1765 91

Triple-negative breast cancers, which represent 10-20% of all mammary tumours, are characterised by the aggressive phenotype, are often found in younger women and have been associated with poor prognosis. Obesity increases the risk for triple-negative breast cancer development. Because triple-negative breast cancer patients are unresponsive to current targeted therapies and other treatment options are only partially effective, new pharmacological modalities are urgently needed. Here we examined if the leptin (obesity hormone) receptor is a viable target for the treatment of this cancer subtype. In human triple-negative breast cancer tissues, the leptin receptor was expressed in 92% (64/69) and leptin in 86% (59/69) of cases. In a model triple-negative breast cancer cell line MDA-MB-231, the leptin receptor antagonist peptide Allo-aca inhibited leptin-induced proliferation at 50 pM concentration. In an MDA-MB-231 orthotopic mouse xenograft model, Allo-aca administered subcutaneously significantly extended the average survival time from 15.4 days (untreated controls) to 24 and 28.1 days at 0.1 and 1mg/kg/day doses, respectively. In parallel, conventional treatment with 1mg/kg/day intraperitoneal cisplatin prolonged the average survival time to 18.6 days, while administration of 20mg/kg/day oral Tamoxifen (negative control) had no significant survival effects relative to controls. In normal CD-1 mice, Allo-aca produced no systemic toxicity up to the highest studied subcutaneous bolus dose of 50mg/kg, while, as expected, it induced a modest 6-10% body weight increase. Our results indicate that leptin receptor antagonists could become attractive options for triple-negative breast cancer treatment, especially in the obese patient population.
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PMID:Efficacy of a leptin receptor antagonist peptide in a mouse model of triple-negative breast cancer. 2135 30

PHF2 is a JmjC family histone demethylase that removes the methyl group from H3K9me2 and works as a coactivator for several metabolism-related transcription factors. In this study, we examined the in vivo role of PHF2 in mice. We generated Phf2 floxed mice, systemic Phf2 null mice by crossing Phf2 floxed mice with CMV-Cre transgenic mice, and tamoxifen-inducible Phf2 knockout mice by crossing Phf2 floxed mice with Cre-ERT2 transgenic mice. Systemic Phf2 null mice had partial neonatal death and growth retardation and exhibited less adipose tissue and reduced adipocyte numbers compared with control littermates. Tamoxifen-induced conditional knockout of PHF2 resulted in impaired adipogenesis in stromal vascular cells from the adipose tissue of tamoxifen-inducible Phf2 knockout mice as well as of Phf2 knocked-down 3T3-L1 cells. PHF2 interacts with CEBPA and demethylates H3K9me2 in the promoters of CEBPA-regulated adipogenic genes. These findings suggest that PHF2 histone demethylase potentiates adipogenesis through interaction with CEBPA in vivo. Taken together, PHF2 may be a novel therapeutic target in the treatment of obesity and the metabolic syndrome.
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PMID:Epigenetic regulation of adipogenesis by PHF2 histone demethylase. 2327 92

As the pandemic of obesity is growing, a variety of animal models have been generated to study the mechanisms underlying the increased adiposity and development of metabolic disorders. Tamoxifen (Tam) is widely used to activate Cre recombinase that spatiotemporally controls target gene expression and regulates adiposity in laboratory animals. However, a critical question remains as to whether Tam itself affects adiposity and possibly confounds the functional study of target genes in adipose tissue. Here we administered Tam to Cre-absent forkhead box O1 (FoxO1) floxed mice (f-FoxO1) and insulin receptor substrate Irs1/Irs2 double floxed mice (df-Irs) and found that Tam induced approximately 30% reduction (P<0.05) in fat mass with insignificant change in body weight. Mechanistically, Tam promoted reactive oxygen species (ROS) production, apoptosis and autophagy, which was associated with downregulation of adipogenic regulator peroxisome proliferator-activated receptor gamma and dedifferentiation of mature adipocytes. However, normalization of ROS potently suppressed Tam-induced apoptosis, autophagy and adipocyte dedifferentiation, suggesting that ROS may account, at least in part, for the changes. Importantly, Tam-induced ROS production and fat mass reduction lasted for 4-5 weeks in the f-FoxO1 and df-Irs mice. Our data suggest that Tam reduces fat mass via boosting ROS, thus making a recovery period crucial for posttreatment study.
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PMID:Tamoxifen reduces fat mass by boosting reactive oxygen species. 2556 3

Studies in vitro suggest that mitogen-activated protein kinase kinase kinase kinase 4 (Map4k4) attenuates insulin signaling, but confirmation in vivo is lacking since Map4k4 knockout is lethal during embryogenesis. We thus generated mice with floxed Map4k4 alleles and a tamoxifen-inducible Cre/ERT2 recombinase under the control of the ubiquitin C promoter to induce whole-body Map4k4 deletion after these animals reached maturity. Tamoxifen administration to these mice induced Map4k4 deletion in all tissues examined, causing decreased fasting blood glucose concentrations and enhanced insulin signaling to AKT in adipose tissue and liver but not in skeletal muscle. Surprisingly, however, mice generated with a conditional Map4k4 deletion in adiponectin-positive adipocytes or in albumin-positive hepatocytes displayed no detectable metabolic phenotypes. Instead, mice with Map4k4 deleted in Myf5-positive tissues, including all skeletal muscles tested, were protected from obesity-induced glucose intolerance and insulin resistance. Remarkably, these mice also showed increased insulin sensitivity in adipose tissue but not skeletal muscle, similar to the metabolic phenotypes observed in inducible whole-body knockout mice. Taken together, these results indicate that (i) Map4k4 controls a pathway in Myf5-positive cells that suppresses whole-body insulin sensitivity and (ii) Map4k4 is a potential therapeutic target for improving glucose tolerance and insulin sensitivity in type 2 diabetes.
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PMID:Inducible Deletion of Protein Kinase Map4k4 in Obese Mice Improves Insulin Sensitivity in Liver and Adipose Tissues. 2591 48

Insulin resistance is a common feature of obesity and predisposes individuals to various prevalent pathological conditions. G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptor kinase 2 (GRK2) integrates several signal transduction pathways and is emerging as a physiologically relevant inhibitor of insulin signaling. GRK2 abundance is increased in humans with metabolic syndrome and in different murine models of insulin resistance. To support GRK2 as a potential drug target in type 2 diabetes and obesity, we investigated whether lowering GRK2 abundance reversed an ongoing systemic insulin-resistant phenotype, using a mouse model of tamoxifen-induced GRK2 ablation after high-fat diet-dependent obesity and insulin resistance. Tamoxifen-triggered GRK2 deletion impeded further body weight gain, normalized fasting glycemia, improved glucose tolerance, and was associated with preserved insulin sensitivity in skeletal muscle and liver, thereby maintaining whole-body glucose homeostasis. Moreover, when continued to be fed a high-fat diet, these animals displayed reduced fat mass and smaller adipocytes, were resistant to the development of liver steatosis, and showed reduced expression of proinflammatory markers in the liver. Our results indicate that GRK2 acts as a hub to control metabolic functions in different tissues, which is key to controlling insulin resistance development in vivo. These data suggest that inhibiting GRK2 could reverse an established insulin-resistant and obese phenotype, thereby putting forward this enzyme as a potential therapeutic target linking glucose homeostasis and regulation of adiposity.
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PMID:Reversal of diet-induced obesity and insulin resistance by inducible genetic ablation of GRK2. 2619 59

The involvement of tissue ischemia in obesity-induced kidney injury remains to be elucidated. Compared with low fat diet (LFD)-mice, high fat diet (HFD)-fed mice became obese with tubular enlargement, glomerulomegaly and peritubular capillary rarefaction, and exhibited both tubular and glomerular damages. In HFD-fed mice, despite the increase in renal pimonidazole-positive areas, the expressions of the hypoxia-responsive genes such as Prolyl-hydroxylase PHD2, a dominant oxygen sensor, and VEGFA were unchanged indicating impaired hypoxic response. Tamoxifen inducible proximal tubules (PT)-specific Phd2 knockout (Phd2-cKO) mice and their littermate control mice (Control) were created and fed HFD or LFD. Control mice on HFD (Control HFD) exhibited renal damages and renal ischemia with impaired hypoxic response compared with those on LFD. After tamoxifen treatment, HFD-fed knockout mice (Phd2-cKO HFD) had increased peritubular capillaries and the increased expressions of hypoxia responsive genes compared to Control HFD mice. Phd2-cKO HFD also exhibited the mitigation of tubular damages, albuminuria and glomerulomegaly. In human PT cells, the increased expressions of hypoxia-inducible genes in hypoxic condition were attenuated by free fatty acids. Thus, aberrant hypoxic responses due to dysfunction of PHD2 caused both glomerular and tubular damages in HFD-induced obese mice. Phd2-inactivation provides a novel strategy against obesity-induced kidney injury.
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PMID:Obesity-induced kidney injury is attenuated by amelioration of aberrant PHD2 activation in proximal tubules. 2782 16

Modifiable lifestyle factors may reduce the risk of developing breast cancer. Obesity is associated particularly with post-menopausal breast cancer. Diet is important, and exercise equivalent to running for up to 8 hours each week reduces the risk of breast cancer, both in its own right and through reducing obesity. Alcohol consumption may be responsible for 5.8% of breast cancers in Australia and it is recommended to reduce this to two standard drinks per day. Drinking alcohol and smoking increases the risk for breast cancer and, therefore, it is important to quit tobacco smoking. Prolonged use of combined oestrogen and progesterone hormone replacement therapy and oral contraceptives may increase breast cancer risk and this must be factored into individual decisions about their use. Ionising radiation, either from diagnostic or therapeutic radiation or through occupational exposure, is associated with a high incidence of breast cancer and exposure may be reduced in some cases. Tamoxifen chemoprevention may reduce the incidence of oestrogen receptor positive cancer in 51% of women with high risk of breast cancer. Uncommon but serious side effects include thromboembolism and uterine cancer. Raloxifene, which can also reduce osteoporosis, can be used in post-menopausal women and is not associated with the development of uterine cancer. Surgical prophylaxis with bilateral mastectomy and salpingo-oophorectomy can reduce the risk of breast cancer in patients carrying BRCA1 or BRCA2 mutations. For preventive treatments, mammographic screening can identify other women at high risk.
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PMID:Prevention of breast cancer. 2785 87


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