Postmenopausal Obesity Research Articles

Association between common risk factors and molecular subtypes in breast cancer patients

BackgroundBreast cancer is the most commonly diagnosed cancer in women worldwide and characterized its by molecular and clinical heterogeneity. Gene expression profiling studies have classified breast cancers into five subtypes: luminal A, luminal B, HER-2 overexpressing, basal-like, and normal breast-like. Although clinical differences between subtypes have been well described in the literature, etiologic heterogeneity have not been fully studied. The aim of this study was to assess the associations between several hormonal and nonhormonal risk factors and molecular subtypes of breast cancer. MethodsThis cross-sectional study consisted of 1884 invasive breast cancer cases. Variables studied included family history, age at first full-term pregnancy, number of children, duration of lactation, menstruation history, menopausal status, blood type, smoking, obesity, oral contraceptive use, hormone replacement therapy and in vitro fertilization. The odds ratios (OR) and 95% confidence intervals (CI) were estimated using multivariate logistic regression analysis. ResultsThousand two-hundred and forty nine patients had luminal A, 234 had luminal B, 169 had HER-2 overexpressing and 232 had triple negative breast cancer. The age of ≥40 years was found to be a risk factor for luminal A (OR 1.41 95% CI 1.15–1.74; p=0.001) and HER-2 overexpressing subtype (OR: 1.51, 95% CI: 1.01–2.25; p=0.04). Women who were nulliparous (OR 1.48, 95% CI 1.03–2.13; p=0.03) or who had their first full-term pregnancy at age 30 years or older (OR 1.25 95% CI 0.83–1.88; p=0.04) were at increased risk of luminal breast cancer, whereas women with more than two children had a decreased risk (OR 0.68, 95% CI 0.47–0.97; p=0.03). Breast-feeding was also a protective factor for luminal subtype (OR 0.74, 95% CI 0.53–1.04; p=0.04) when compared to non-luminal breast cancer. We found increased risks for postmenopausal women with HER-2 overexpressing (OR 2.20, 95% CI 0.93–5.17; p=0.04) and luminal A (OR 1.87, 95% CI 0.93–3.90, p=0.02) breast cancers, who used hormone replacement therapy for 5 years or more. Overweight and obesity significantly increased the risk of triple negative subtype (OR 1.89 95% CI 1.06–3.37; p=0.04 and OR 1.90 95% CI 1.00–3.61; p=0.03), on the contrary, decreased the risk of luminal breast cancer (OR 0.63 95% CI 0.43–0.95; p=0.02 and OR 0.50 95% CI 0.32–0.76; p=0.002, respectively) in premenopausal women. There were no significant differences between risk of breast cancer subtypes and early menarche, late menopause, family history, postmenopausal obesity, oral contraseptive use, smoking, in vitro fertilization, blood groups and use of hands. ConclusionsReproductive and hormonal characteristics (breastfeeding, parity, age at first full-term birth, hormone replacement therapy) were associated with luminal subtype, compared to non-luminal breast cancer, as consistent with previous studies. Obesity and overweight increased the risk of triple negative subtype, particularly in premenopausal women. Older age and use of hormone replacement therapy were related to the risk of HER-2 overexpressing breast cancer. Our data suggest a significant heterogeneity in association of traditional breast cancer risk factors and tumor subtypes.

1698P - Do the Well-Known Risk Factors of Breast Cancer Have the Same Impact on Development of Molecular Subtypes?

ABSTRACT Background Altough clinical differences between breast cancer (BC) subtypes have been well-described, etiologic heterogeneity have not been fully studied. The aim of this study was to assess the associations between risk factors and molecular subtypes of BC. Methods 1884 invasive BC cases were retrospectively analyzed. The odds ratios (OR) and 95% confidence intervals (CI) were estimated using multiple logistic regression analysis. Results 1249 patients had luminal A, 234 had luminal B, 169 had HER-2 overexpressing and 232 had triple negative BC. The age of ≥40 years was found to be a risk factor for luminal A (OR 1.41 95% CI 1.15-1.74; p = 0.001) and HER-2 overexpressing subtype (OR:1.51, 95% CI:1.01-2.25; p = 0.04). Women who were nulliparous (OR 1.48, 95% CI 1,03-2,13; p = 0.03) or who had their first full-term pregnancy ≥30 years (OR 1.25 95% CI 0.83-1.88; p = 0.04) were at increased risk of luminal BC, whereas women with >2 children had a decreased risk (OR 0.68, 95% CI 0.47-0.97; p = 0.03). Breast-feeding was a protective factor for luminal BC (OR 0.74, 95% CI 0.53-1.04; p = 0.04). We found increased risks for postmenopausal women with HER-2 overexpressing (OR 2.20, 95% CI 0.93-5.17; p = 0.04) and luminal A (OR 1.87, 95% CI 0.93-3.90, p = 0.02) BC, who used hormone replacement therapy for ≥5 years. Overweight and obesity increased the risk of triple negative BC (OR 1.89 95% CI 1.06-3.37; p = 0.04 and OR 1.90 95% CI 1.00-3.61; p = 0.03), on the contrary, decreased the risk of luminal BC (OR 0.63 95% CI 0.43-0.95; p = 0.02 and OR 0.50 95% CI 0.32-0.76; p = 0.002, respectively) in premenopausal women. There were no significant differences between risk of BC subtypes and early menarche, late menopause, family history, postmenopausal obesity, oral contraseptive use, smoking, in vitro fertilization and blood groups. Conclusions Reproductive and hormonal characteristics were associated with luminal BC. Obesity and overweight increased the risk of triple negative subtype, particularly in premenopausal women. Older age and use of hormone replacement therapy were related to the risk of HER-2 overexpressing BC. Our data suggest a significant heterogeneity in association of traditional BC risk factors and tumor subtypes. Disclosure All authors have declared no conflicts of interest.

Effects of 12-weeks walking exercise on appetite regulating hormone, adipokine and insulin resistance in postmenopausal obesity women

Effects of 12-weeks walking exercise on appetite regulating hormone, adipokine and insulin resistance in postmenopausal obesity women

Simplifying the Energy Balance Message for Breast Cancer Prevention

Simple prevention messages based on understandable biologic principles are likely to be adopted. The long-held premise that postmenopausal obesity elevates, but premenopausal obesity reduces, risk for breast cancer is confusing to the public. Furthermore, decades of positive energy balance may be difficult to suddenly reverse at the time of the menopause. In this issue (beginning on page 583), Cecchini et al. suggest that obesity may also be a risk factor for pre-menopausal women 35 and older who have additional risk factors for breast cancer. Although the relative impact of dysregulated energy metabolism depends on many factors including age, hormonal milieu, and competing risk factors, as well as how it is measured, avoiding weight gain after age 30 is increasingly being recognized as a simple way to reduce risk of breast cancer.

Characteristics of metabolic syndrome in women

Aims. To evaluate combination and manifestation sequence of metabolic syndrome (MS) components, as well as cardiovascular riskfactors in women. Materials and methods. We examined 100 female subjects with MS. We assessed anthropometric parameters, glycemic control andlipid metabolism. We also conducted cardiac ultrasound in all participants. Results. 44% of patients developed abdominal obesity after pregnancy, 48% - in perimenopausal period and in 8% of studied casesobesity manifested in combination with arterial hypertension 10 years before menopause (at the average). Family history of type 2diabetes mellitus and obesity, elevation of LDL and TG characterized post pregnancy abdominal obesity. Postmenopausal obesity wasassociated with significantly lower levels of HDL. HDL concentration was also lower in cases of histerectomia and early age of surgicalmenopause. Conclusion. Manifestation of MS in females is associated with periods of hormonal imbalance. Cardiovascular risk positively correlateswith number of pregnancies, duration of abdominal obesity experience, and negatively - with HDL level and age of surgical menopause.Complete form of MS (with all 6 components present) is found more frequently in women with postmenopausal manifestation.

Body size and the risk of postmenopausal breast cancer subtypes in the California Teachers Study cohort.

PURPOSE: To evaluate how the association between body size and breast cancer risk varies by tumor receptor subtype, host factors, and other exposures among women in the California Teachers Study cohort. METHODS: Among 52,642 postmenopausal women, 2,321 developed invasive breast cancer with known estrogen- and progesterone-receptor status (1,652 ER+PR+, 338 ER+PR-, and 312 ER-PR-) between 1995 and 2007. In a subset of 35,529 with waist circumference data, 1,377 developed invasive breast cancer with known ERPR status (991 ER+PR+, 208 ER+PR-, 169 ER-PR-) between 1997 and 2007. Multivariate Cox regression was performed to estimate relative risks (RR) and 95% confidence intervals (CI). RESULTS: Obesity, adult weight gain of ≥40 pounds, greater abdominal adiposity, and greater height increased the risk of ER+PR+ breast cancer. The increased risk associated with postmenopausal obesity was limited to those who did not use hormone therapy (HT) at cohort entry (RR=1.37; 95% CI, 1.05-1.78 for BMI≥30 vs.<25kg/m(2); p-interaction=0.14) and those who were not overweight or obese at age 18 (p-interaction=0.06). The increased risk associated with greater abdominal adiposity was limited to those who were not also overweight or obese (p-interaction=0.01). Neither obesity, abdominal adiposity, nor height was associated with the risk of ER-PR- tumors. CONCLUSIONS: The effects of body size on postmenopausal breast cancer risk differed by hormone receptor subtype, and among women with ER+PR+ tumors, by HT use and early adult body size.

Should diabetic women with breast cancer have their own intervention studies?

This commentary on 'Calorie restriction and rapamycin inhibit MMTV-Wnt-1 mammary tumor growth in a mouse model of postmenopausal obesity' by Nogueira et al., published in this issue of Endocrine-Related Cancer, addresses the challenges of translating diet, exercise, and pharmacologic trials in diabetic mouse mammary tumor models to human studies. We propose that trials specifically designed to test such interventions in diabetic women with breast cancer would be valuable and informative.

P4-03-02: High Fat Diet-Induced Postmenopausal Obesity Promotes Tumor Angiogenesis and Breast Cancer Progression in Age-Relevant Ovariectomized Mice.

Abstract Background: Obese postmenopausal women have 50% higher risk of breast cancer than non-obese women. The mechanisms of postmenopausal obesity-induced breast cancer are poorly understood due to lack of the established animal model that mimics postmenopausal obesity related to breast cancer progression. Material and Methods: Using age-relevant C57BL/6 mice, this study determined whether postmenopausal obesity increases VEGF expression, tumor angiogenesis, and breast tumor growth. Ovariectomy (OVX) was performed in 12 sixty week-old female mice (life span is about 140 weeks), then followed by a low-fat (5%, LF, n=6) or a high-fat (60%, HF, n=6) diet for 12 weeks. In the 8th wk of the dietary program, 10^6 E0771 (mouse breast cancer) cells were injected in the left fourth mammary gland. Tumor size was monitored using dial calipers for 4 wk. Body weights were monitored weekly. At the end of the experiment, blood samples, visceral fat, and tumors were collected for measuring VEGF expression using ELISA and intratumoral microvessel density (IMD) using CD31 immunochemistry. Results: Body weight was significantly increased in OVX/HF mice, compared to OVX/LF group (55.3±1.7 vs. 41.5±1.5 g; P&amp;lt;0.01). There was a two-fold increase in the ratio of visceral fat/BW in OVX/HF mice, compared to those in OVX/LF group (0.062±0.005 vs. 0.032±0.003; P&amp;lt;0.01). Postmenopausal obesity significantly increased breast tumor weight over the control (4.62±0.63 vs. 1.98±0.27 g; P&amp;lt;0.01) and IMD (173±3.7 vs. 139±4.3 IM#/mm^2; P&amp;lt;0.01). Tumor VEGF levels were higher in OVX/HF mice, compared to OVX/LF group (73.3±3.8 vs. 49.5±4.3 pg/mg protein; P&amp;lt;0.01). Plasma VEGF levels (69±7.1 vs. 48±3.5 pg/ml) and visceral fat VEGF levels (424.4±39.5 vs. 208.5±22.4 pg/mg protein) were significantly increased in OVX/HF mice, compared to OVX/LF group, respectively (n=6; P&amp;lt;0.01). Interestingly, adipose tissue primary culture showed that subcutaneous fat released more VEGF, compared to visceral fat (6.77±1.14 vs. 0.94±0.16 pg/mg tissue; n=6; P&amp;lt;0.01). The abdominal subcutaneous fat expressed more VEGF proteins than visceral fat in OVX/HF mice (692±72 vs. 431±44 pg/mg protein; n=6; P&amp;lt;0.01). There was a strong positive linear correlation between increased breast tumor weight and visceral fat weight in OVX mice (R2=0.7379; N=12; P&amp;lt;0.01). However, there was no significant difference in heart, or kidney weight/body weight ratio between postmenopausal obesity (OVX/HF) mice and the control mice (OVX/LF). Discussion: Our observations indicate that ovariectomy plus a high fat diet with the inoculation of E0771 (mouse ER+ breast cancer) cells in female wild type &amp;gt;60 week old mice can mimic human obesity-induced postmenopausal breast cancer. The increased tumor angiogenesis in postmenopausal obese mice was correlated with increased breast tumor growth, adipose tissue mass, and adipokines such as VEGF. These findings support the hypothesis that postmenopausal obesity promotes tumor angiogenesis and breast cancer progression, possibly through increased adipose tissue mass and adipokines such as VEGF that could systemically and locally affect breast cancer progression. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-03-02.

Calorie restriction and rapamycin inhibit MMTV-Wnt-1 mammary tumor growth in a mouse model of postmenopausal obesity

Obesity is an established risk and progression factor for postmenopausal breast cancer. Interventions to decrease caloric intake and/or increase energy expenditure beneficially impact tumor progression in normoweight humans and animal models. However, despite the increasingly high global prevalence of obesity, the effects and underlying mechanisms of these energy balance modulating interventions are poorly characterized in obese individuals. The goal of this study was to better characterize the mechanism(s) responsible for the link between energy balance and breast cancer progression in the postmenopausal obesity context. We compared the effects of calorie restriction (CR), treadmill exercise (EX), and mammalian target of rapamycin (mTOR inhibitor) treatment on body composition, serum biomarkers, cellular signaling, and mammary tumor growth in obese mice. Ovariectomized C57BL/6 mice were administered a diet-induced obesity regimen for 8 weeks, then randomized into three treatment groups: control (semipurified diet fed ad libitum, maintained the obese state); 30% CR (isonutrient relative to control except 30% reduction in carbohydrate calories); and EX (control diet fed ad libitum plus treadmill exercise). Mice were implanted with syngeneic MMTV-Wnt-1 mammary tumor cells at week 12. Rapamycin treatment (5 mg/kg every 48 h) started at week 14. Tumors were excised at week 18. CR and rapamycin (but not EX) significantly reduced final tumor weight compared to control. In follow-up analysis, constitutive activation of mTOR ablated the inhibitory effects of CR on Wnt-1 mammary tumor growth. We conclude that mTOR inhibition may be a pharmacologic strategy to mimic the anticancer effects of CR and break the obesity-breast cancer progression link.

Abstract A75: Calorie restriction and rapamycin, but not exercise, inhibit mammary tumor growth in a mouse model of postmenopausal obesity

Abstract Obesity is a well-established risk factor for postmenopausal breast cancer and is associated with poor outcomes in both premenopausal and postmenopausal women. Given that approximately one third of the US population is obese, interventions to reverse the detrimental effects of obesity on breast cancer progression are urgently needed. The molecular target of Rapamycin (mTOR) modulates pathways regulating energy balance and cell growth. Therefore, agents that target the mTOR pathway are promising for breaking the obesity-breast cancer link. Here, we directly compared the two most recommended strategies for reversing obesity, calorie restriction (CR) and exercise (EX), and a well-established mTOR inhibitor (rapamycin) on mammary tumor growth and metabolic profiles in obese mice. Ovariectomized C57BL/6 mice were administered a diet-induced obesity regimen for 8 weeks, then randomized into 3 diet or exercise treatment groups: Control (AIN-76A diet fed ad libitum to maintain the obese state, n=30); 30% CR (70% of the carbohydrate calories but otherwise isonutrient relative to control, n=15); EX (control diet fed ad libitum plus treadmill exercise regimen, n=15). Mice were orthotopically implanted (4th mammary gland) with syngeneic MMTV-Wnt-1 mammary tumor cells at week 12. Of the 30 mice in the control group, 15 received rapamycin (5mg/kg, administered ip every 48hrs) starting at week 14. All other mice received vehicle treatment (saline, administered ip every 48 hrs) starting at week 14. Tumors were excised at week 18. Final tumor weights from mice in the CR (0.043 ± 0.007 g) and rapamycin (0.072 ± 0.010 g) groups, but not EX (0.380 ± 0.072 g) group, were significantly reduced compared to control (0.390 ± 0.066 g). The crucial role of mTOR in the link between obesity and breast cancer progression was confirmed in a follow up study where constitutive activation of mTOR (mTOR) ablated the inhibitory effects of CR on mammary tumor growth. CR failed to reduce tumor weight in mice injected with cells transfected with mTOR (0.38 ± 0.05 g), compared to control (0.55 ± 0.08 g). Transfection effect bias was discarded since CR significantly reduced weight of tumors (0.29 ± 0.03 g) in mice injected with cells transfected with WT mTOR, compared to control (0.62 ± 0.12 g). We conclude that mTOR inhibition may be a pharmacologic strategy to mimic the anticancer effects of CR and break the obesity-breast cancer progression link. Citation Information: Cancer Prev Res 2011;4(10 Suppl):A75.

Serum levels of ischemia modified albumin in overweight/obese postmenopausal women: A potential biomarker of atherosclerotic burden associated with oxidative stress

Objective Menopause is associated with weight gain and an increase of cardiovascular risk. The aim of the present study was to estimate serum ischemia-modified albumin (IMA) levels in postmenopausal women and evaluate their association with body mass index (BMI) and coronary artery disease (CAD). Methods The study included 130 non-smoker postmenopausal women aged 43–80: 40 with BMI 26–32 kg/m 2 (Group A), 60 with BMI 21–25 kg/m 2 (Group B), and 30 with documented CAD and BMI 23–29 kg/m 2 (Group C). Serum IMA, albumin, hsCRP and NT-proBNP, glucose and insulin were measured. Homeostasis assessment model score (HOMA) and Quantitative insulin sensitivity index (QUICKI) were co-estimated. Results Serum IMA and IMA to albumin ratio were significantly elevated in Group A as compared to Group B ( p < 0.001) and similar to those of Group C. hsCRP and NT-proBNP did not differ between Groups A and B while they were lower in comparison to Group C ( p < 0.001). Glucose, insulin and HOMA were elevated in Group A compared to Group B ( p < 0.001) while QUICKI was lower ( p < 0.001). In Group A, IMA was positively correlated with BMI, hsCRP, insulin, HOMA and negatively with QUICKI. In postmenopausal women, multivariable regression analysis revealed that obesity was the strongest significant determinant of circulating IMA levels ( p < 0.001) contributing, therefore, to the elevated serum IMA concentration. Conclusions Postmenopausal obesity is associated with elevated serum IMA possibly due to obesity associated oxidative stress. IMA measurement could provide an assessment of atherosclerotic burden in postmenopausal women. Further clinical evaluation is under investigation.

The Peptidic GHS-R antagonist [D-Lys3]GHRP-6 markedly improves adiposity and related metabolic abnormalities in a mouse model of postmenopausal obesity

It was demonstrated that estrogen deficiency and consuming high fat (HF) diet enhanced orexigenic activity of ghrelin. Therefore, we hypothesized that antagonizing of ghrelin action would attenuate food intake and body weight in mice obese both from ovariectomy (OVX) and feeding a HF diet.Ghrelin receptor antagonist [D-Lys3]GHRP-6 after seven days of subcutaneous treatment markedly decreased food intake in OVX mice fed both HF and standard diets; furthermore, it reduced body weight and blood glucose, insulin and leptin, and increased β-hydroxybutyrate level and uncoupling-protein-1 mRNA in brown adipose tissue. Pair-feeding revealed that effect of [D-Lys3]GHRP-6 was primary anorexigenic. Estrogen supplementation reduced anorexigenic effects of [D-Lys3]GHRP-6. OVX [D-Lys3]GHRP-6 treatment in mice on HF diet resulted in markedly increased circulating level and liver expression of a major metabolic regulator, fibroblast growth factor 21.Our data suggest that ghrelin antagonists could be especially beneficial in individuals with common obesity combined with estrogen deficiency.

Postmenopausal obesity promotes tumor angiogenesis and breast cancer progression in mice

Obese postmenopausal women have a 50% higher risk of breast cancer than non-obese women. There is not an animal model that mimics postmenopausal obesity related to breast cancer progression. Using age-relevant C57BL/6 mice, this study determined whether postmenopausal obesity increases VEGF expression, tumor angiogenesis, and breast tumor growth. Ovariectomy (OVX) was performed in 12 sixty week-old female mice, then followed by a low-fat (5%, LF, n=6) or a high-fat (60%, HF, n=6) diet for 12 weeks. In the eighth week of the dietary program, 10^6 E0771 (mouse breast cancer) cells were injected in the left fourth mammary gland. Tumor size was monitored for 4 weeks. Body weights were monitored weekly. At the end of the experiment, blood samples, visceral fat and tumors were collected for measuring VEGF expression using ELISA and intratumoral microvessel density (IMD) using CD31 immunochemistry. Body weight was significantly increased in OVX/HF mice, compared to OVX/LF group (55.3±1.7 vs. 41.5±1.5 g; p < 0.01). There was a two-fold increase in the ratio of visceral fat/BW in OVX/HF mice, compared to those in OVX/LF group (0.062±0.005 vs. 0.032±0.003; p < 0.01). Postmenopausal obesity significantly increased breast tumor weight over the control (4.62±0.63 vs. 1.98±0.27 g; p < 0.01) and IMD (173±3.7 vs. 139±4.3 IM#/mm^2; p < 0.01). Tumor VEGF levels were higher in OVX/HF mice, compared to OVX/LF group (73.3±3.8 vs. 49.5±4.3 pg/mg protein; p < 0.01). Plasma VEGF levels (69±7.1 vs. 48±3.5 pg/ml) and visceral fat VEGF levels (424.4±39.5 vs. 208.5±22.4 pg/mg protein) were significantly increased in OVX/HF mice, compared to OVX/LF group, respectively (n=6; p < 0.01). Interestingly, adipose tissue primary culture showed that subcutaneous fat released more VEGF, compared to visceral fat (6.77±1.14 vs. 0.94±0.16 pg/mg tissue; n=6; p < 0.01). These findings support the hypothesis that postmenopausal obesity promotes tumor angiogenesis and breast cancer progression, possibly through increased adipose tissue mass and adipokines such as VEGF that could systemically and locally affect breast cancer progression.

Postmenopausal obesity promotes tumor angiogenesis and breast cancer progression

Obese postmenopausal women have 50% higher risk of breast cancer than non-obese women. There is no animal model that mimics postmenopausal obesity related to breast cancer progression. This study used age-relevant C57BL/6 mice for determing whether postmenopausal obesity increases VEGF expression, tumor angiogenesis, and breast tumor growth. Ovariectomy (OVX) was performed in 12 sixty week-old female mice, then followed by a low fat (5%, LF, n=6) or a high-fat (60%, HF, n=6) diet for 12 weeks. In the 8th wk of the dietary program, 10^6 E0771 (mouse breast cancer) cells were injected in the left fourth mammary gland, and tumor size was monitored for 4 wk. OVX/HF mice significantly increased body weight (55.3±1.7 vs. 41.5±1.5 g), visceral fat/BW ratio (0.062±0.005 vs. 0.032±0.003), tumor weight (4.62±0.63 vs. 1.98±0.27 g), plasma VEGF levels (69±7.1 vs. 48±3.5 pg/ml), visceral fat VEGF levels (424.4±39.5 vs. 208.5±22.4 pg/mg protein), tumor VEGF levels (73.3±3.8 vs. 49.5±4.3 pg/mg protein), and intratumoral microvessel density (173±3.7 vs. 139±4.3 IM#/mm^2), compared to OVX/LF group, respectively (n=6; P<0.01). These findings support the hypothesis that postmenopausal obesity promotes tumor angiogenesis and breast cancer progression, possibly through increased adipose tissue mass and adipokines such as VEGF that could systemically and locally affect breast cancer progression.

Amylin May Offer (More) Help to Treat Postmenopausal Obesity

The modern world faces an exploding obesity epidemic, and despite many years of intensive research, the current clinically available nonsurgical treatment strategies are rather unsuccessful and drugs that were expected to alleviate the obesity problem had to be withdrawn from the market. Hence, understanding the physiological controls of eating has never been more important; this understanding may potentially help to develop effective pharmacological tools that reduce eating and eventually body weight without unacceptable side effects. Obesity research has to a large extent been focused on central nervous system neurotransmitters and also on long-term adiposity signals; the controls of individual meals were less in that focus, but it is now recognized that adiposity signals influence eating by modulating the effect of meal size controls (e.g. Refs. 1 and 2). The effects of adiposity signals and meal size controls appear to exhibit sex differences, and at least in females, estradiol appears to be the major factor that is involved in the control of eating, mainly by modulating meal size controls (3–6). Basic research on the estrogenic inhibition of eating is of great health relevance. This research is expected to promote our understanding of disordered control of meal size in human eating disorders; women seem to be disproportionately more vulnerable to these disorders than men (7– 9). These disorders include anorexia nervosa, bulimia nervosa, and binge-eating disorder, which is an important contributor to obesity. Further, morbid obesity is more prevalent in women than men (10). Estradiol has been shown to control eating and body weight mainly via modulating the potency of feedback signals that control meal size (5, 6). The best investigated interaction is that between cholecystokinin (CCK) and estradiol; the data indicate that estradiol increases the satiating potency of exogenous and endogenous CCK (11– 13). Similar mechanisms may be operational for glucagon because the effects of glucagon and of glucagon antibodies to decrease or increase meal size, respectively, were both amplified by estradiol in ovariectomized (OVX) rats (14). Finally, our own unpublished data indicate that estradiol enhanced the acute eating inhibitory effect of exogenous amylin in OVX rats (Asarian L., N. Geary, and T. Lutz, unpublished observations). It is a well-established phenomenon that the absence of estradiol leads to a temporary increase in eating and a sustained increase in body weight (5, 9, 11). This phenomenon is of clinical relevance because estradiol levels decrease in postmenopausal women; importantly, postmenopausal women make up a high percentage of the obese population. Because most nonsurgical treatment options for obese people have been withdrawn from the market due to unacceptable side effects, the amylin-based combination therapy with leptin has raised increased interest as an effective antiobesity treatment. The recent paper by Trevaskis et al. (15) provides new and to a large extent surprising insight into the role of estradiol in the control of eating, in particular in terms of estradiol’s interaction with chronic amylin treatment. Trevaskis et al. used diet-induced obese (DIO) female rats that were OVX; part of the OVX rats received cyclic estradiol replacement that mimics the physiology of an intact female sexual cycle (16). Several key findings reported in this paper are worth mentioning here. Similar to previous studies in intact male DIO rats (17; see also Ref. 18), amylin reduced the body weight gain in sexually intact female sham-operated DIO rats. The effect was similar in OVX rats that received physiological estradiol replacement therapy; interestingly, amy-

Evaluation of Intervention Research in Weight Reduction in Post Menopausal Women

To describe the evidence that has accrued for interventions targeting weight loss in postmenopausal women, and to assess the strengths and limitations of weight loss interventions in postmenopausal women using the framework of evaluation theory, including definition of the problem and the use of theoretical framework and mediators. Electronic databases were used, including CINAHL, EBSCO Host, Google scholar, Medline, and the Science Citation Index, Expanded, in the Web of Science from 1995 to December 2009. Keyword searches included the terms obesity, obese, overweight, menopause, and weight management interventions. Searches were combined to find reports addressing 1 or more keywords. Experimental design studies that examined physical activity or dietary intervention effects on weight loss or body composition changes in postmenopausal women were selected for review. Reports of 15 intervention studies met inclusion criteria from the list of 120 generated through the database searches. Each article was evaluated for 1) effects produced as a result of the intervention, 2) the characteristics of the problem of postmenopausal obesity, 3) specification of theoretical constructs and critical inputs that guide the design of an intervention, and 4) link of the theoretical predictors and the outcome measures selected. Four types of interventions were tested in the 15 research reports. Only 5 of the 15 used theories or models to guide the interventions. All of the interventions resulted in some positive weight management outcome, such as lowered body mass index, fat mass, waist circumference, systolic blood pressure, glucose, and cholesterol. Overall, the reviewed research showed efficacy of varying intensities of exercise when combined with hypocaloric diet or meal replacement therapy in producing low body weight, low fat, improved insulin sensitivity, glycemic control, and cardio-respiratory fitness. The external validity of the 15 studies was limited in reporting of a clear delineation of the problem, theoretical frameworks, and application of the findings.

Abstract 5084: Treadmill exercise modulates AMP-activated protein kinase and downstream signaling in mammary gland of p53+/−, but not p53+/+ mice

Abstract Epidemiological data show that exercise is generally protective against breast cancer. Inhibition of mammalian target of rapamyocin (mTOR) through activation of AMP-activated protein kinase (AMPK) has been shown to be responsive to exercise. Decreased activation of ribosomal protein S6, a marker for mTOR inhibition, is associated with decreased growth and proliferation. Recently, this energy-sensing pathway has been shown to be inhibited by increased production of reactive oxygen species (ROS) leading to AMPK activation. ROS levels are maintained by p53-inducible anti-oxidant enzymes. Therefore, we hypothesized that energy sensing pathways that mediate the protective effects of exercise in breast cancer are modulated by p53 gene dosage. To test this hypothesis, we fed ovariectomized mice a high-fat diet (60% kcal) ad libitum for 10 weeks to model post-menopausal obesity. Mice were then randomized to a sedentary or exercise regimen (n=15/group). Exercised mice ran on a variable speed treadmill (5% incline, 20 m/min, 40 min/day, 5 days/week for 22 weeks). Changes in percent body fat were measured every 2 weeks using quantitative magnetic resonance. Immunoblot analysis was performed to measure phosphorylation of AMPK (Thr 172) and ribosomal protein S6 (Ser 240/244) relative to total levels in the mammary fat pad (MFP). Also, qRT-PCR was performed to measure mRNA expression of the p53-inducible anti-oxidant enzyme sestrin 1. At the end of the diet-induced obesity regimen, there was no effect of p53 genotype on percent body fat (54.4 ± 0.7 in p53+/+ versus 55.9 ± 1.1 in p53+/−). After 22 weeks of exercise, the EX mice displayed signficantly less percent body fat than sedentary controls, with no effect of genotype (44.4 ± 0.6 versus 47.8 ± 0.8 % respectively, p&amp;lt;0.05). Immunoblot analysis revealed that in p53+/− mice, but not p53+/+ mice, exercise increased AMPK phosphorylation. This increased AMPK phosphorylation was associated with decreased phosphorylation of ribosomal protein S6, a marker of mTOR pathway activation (n=3/group). The observed increase in AMPK phosphorylation in p53+/− exercised mice relative to sedentary p53+/− was associated with decreased mRNA levels of sestrin 1 (n=4-6/group), indicating that the p53+/− mice may have higher levels of ROS in the MFP. In conclusion, exercise may increase AMPK activation in MFP of p53+/− mice relative to sedentary p53+/− mice through an ROS-mediated mechanism. Current analysis is focused on understanding how exercise affects AMPK activation in the mammary fat pad of MMTV-Wnt-1 transgenic mice heterozygous for p53, and how this impacts mammary tumorigenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5084.

Abstract 2930: Calorie restriction and rapamycin, but not exercise, inhibit MMTV-Wnt-1 mammary tumor growth in a mouse model of postmenopausal obesity

Abstract Obesity is an established breast cancer risk factor in postmenopausal women, and calorie restriction (CR) and exercise (EX) are the two most recommended ways to prevent or reverse obesity. The mammalian Target of Rapamycin (mTOR) pathway is a potential mechanistic target underlying the effects of these interventions, and rapamycin (mTOR inhibitor) has been shown to mimic many of the anticancer effects of CR. However, the effects of obesity reversal by CR, EX, or treatment with rapamycin, on mammary tumor development have not been well studied. Therefore, we administered a diet-induced obesity regimen to 60 ovariectomized C57BL/6 mice for 8 weeks to induce obesity. The mice were then randomized into 4 groups (n=15/group): Control (AIN-76A diet ad libitum); CR (30% calorie restriction relative to control); EX (control diet ad libitum + treadmill exercise at 20m/min, 45min/day, 5days/week); and Rapamycin (control diet ad libitum + 5mg/kg injected i.p. every 48 hrs). Body weight and total body fat were measured every two weeks (using MRI). All mice were injected (4th mammary fat pad) with 5 × 104 MMTV-Wnt-1 mammary tumor cells at week 12, and at week 18 tumors were extracted and analyzed by immunohistochemistry (IHC). At the end of the study, mice in the CR group weighed significantly less (27.6 ± 2.6 g) and displayed lower percent body fat (34.7 ± 5.2 %) than mice in the control group (41.7 ± 2.9 g and 47.9 ± 1.8 %). There were no differences in body weigh or percent body fat in the EX (38.3 ± 3.10 g and 45.9 ± 2.6 %) and Rapamycin (37.4 ± 2.7 g and 46.6 ± 5.6 %) groups compared to control. At the end of the study, the CR and Rapamycin groups had comparable tumor weights (0.04 ± 0.02 g and 0.07 ± 0.04 g) that were significantly smaller than those in the control and EX groups (both 0.3 ± 0.2 g and 0.3 ± 0.2 g). IHC analysis showed that Rapamycin significantly reduced p-mTOR, Cyclin D1 and p-S6 Ribosomal Protein (markers of mTOR activation) compared to control, Exercise and CR. Exercise displayed variable levels of p-mTOR, Cyclin D1 and p-S6 and CR displayed no differences compared to control. Rapamycin tumors were bimodal for both p-Akt (upstream of mTOR) and Ki67 (proliferation marker); those tumors displaying high p-Akt (∼50%) also displayed high Ki67 staining, but tumors with low pAkt displayed low Ki67 staining. CR and Exercise had no effect on p-Akt and Ki67 compared to control. There were no differences in Cleaved-Caspase 3 (marker of apoptosis) between the groups. We conclude that CR and Rapamycin reverse the effects of obesity on Wnt-1 mammary tumor growth, but apparently via different mechanisms, while EX does not appear to have anti-tumor growth effects in obese mice. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2930.

Effect of Variations in Body Mass Index on Serum Leptin Levels in Pre and Post Menopausal Women

Objective: To measure the serum leptin and insulin levels and assess that how body mass index and affects theselevels in pre and post menopausal obese and non-obese women.Place and duration of study: It was a comparative study. Sampling was done from various Hospitals,organizations and residential areas. The experimental work was carried out at the department of Biochemistry &Molecular Biology and Center for Research in Experimental and Applied Medicine-1 (CREAM-1), NUST,Rawalpindi, Pakistan and was spread on duration of 18 months.Methodology: The samples for the study were obtained from healthy eighty subjects & divided intopremenopausal and postmenopausal groups of 40 each which were further sub-divided into obese and non obesebased on the body mass index (cutoff BMI value = 25 kg/m²). Fasting blood sugar, triglycerides, serum Insulinand serum leptin were measured along with BMI and HOMA IR. Data was analyzed for frequencies, percentages,means and standard deviation (± SD). The Chi-square test was used for comparison of qualitative data variablesbetween groups, while the Student’s t-test was used for comparison of means. Linear correlations wereperformed by using the Pearson’s Correlation Coefficient, r.Results: There is significant difference in the mean age, weight, BMI and insulin between the two non-obesegroups. A significant difference in the mean age and triglyceride between the two obese groups was alsoobserved. There is significant difference in the mean age, weight and BMI between the pre menopausalnon-obese and obese groups along with a significant difference in the mean weight, BMI, insulin and HOMA IRbetween the postmenopausal non-obese and obese groups. Leptin has significant positive correlation with weight,BMI, and HOMA IR whereas Insulin has significant positive correlation with weight, leptin and HOMA IR.Conclusion: Menopause does not influence FSL levels. The variations observed in FSL levels between pre andpostmenopausal women, in some studies, might be due to differences in their mean FSI levels and BMI. Themean FSL tends to increase with increased BMI irrespective of menopausal status. There is correspondingincrease in FSL with increase in FSI levels, generally the obese have higher FSI and FSL levels, irrespective ofmenopausal status. Major metabolic hormones insulin and leptin, don’t seem to have a role in pathophysiologyof postmenopausal obesity.

Clinical Observations on Laser Acupuncture in Simple Obesity Therapy

A previous study has shown that laser acupuncture is a useful healing method for the treatment of visceral postmenopausal obesity in combination with a low-calorie diet. We observe and evaluate the therapeutic effect of laser acupuncture in subjects of simple obesity with a non-restrictive diet protocol. Subjects included 73 women and 22 men with simple obesity and body mass indices > or = 27 kg/m2. Daily energy intake recommendations for obese females and males were 1620.0 and 1894.2 kcal in average, respectively. The gallium aluminum arsenide Handylaser Trion was used to apply 0.25 J of energy to each of the following acupuncture points three times per week for four consecutive weeks: Stomach, Hunger, ST25, ST28, ST40, SP15, and CV9. The subjects' body weights and body mass indices were recorded before treatment, and four weeks after treatment, and the percent reduction in each parameter was calculated. Statistically significant reductions in body weight and body mass index were detected after four weeks of treatment. The mean reduction and mean percent reduction in body weight were 3.17 kg and 3.80% (p < 0.0001), respectively. The corresponding values for the body mass index were 1.22 kg/m2 and 3.78% (p < 0.0001), respectively. We concluded that laser acupuncture was found to exert a therapeutic effect on simple obesity by reducing both body weight and body mass index. Moreover, subjects showed good compliance with this comfortable and non-restrictive diet protocol.