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1.  Effects of Energy Restriction and Wheel Running on Mammary Carcinogenesis and Host Systemic Factors in a Rat Model 
Limiting energy availability via diet or physical activity has health benefits; however, it is not known if these interventions have similar effects on the development of cancer. Two questions were addressed: 1) does limiting energy availability by increasing physical activity have the same effect on mammary carcinogenesis as limiting caloric intake, and 2) are host systemic factors, implicated as risk biomarkers for breast cancer, similarly affected by these interventions? Female Sprague Dawley rats were injected with 50 mg 1-methyl-1-nitrosourea/kg body weight at 21 days of age and randomized to one of five groups (30 rats/gp): 1) sham running wheel control; 2) restricted fed to 85% of the sham-control, 3 and 4) voluntary running in a motorized activity wheel (37 m/min) to a maximum of 3500 m/day or 1750 m/day, and 5) sedentary ad libitum fed control with no access to a running wheel. The three energetics interventions inhibited the carcinogenic response, reducing cancer incidence (P=0.01), cancer multiplicity (P<0.001), and cancer burden (P<0.001), while prolonging cancer latency (P=0.004) although differences among energetics interventions were not significant. Of the plasma biomarkers associated with the development of cancer, the energetics interventions reduced bioavailable insulin-like growth factor-1(IGF-1), insulin, interleukin-6, serum amyloid protein, tumor necrosis factor-α, and leptin and increased IGF binding protein 3 (IGFBP3) and adiponection. Plasma fasting glucose, C-reactive protein, estradiol, and progesterone were unaffected. The plasma biomarkers of greatest value in predicting the carcinogenic response were: adiponectin > IGF-1/IGFBP-3 > IGFBP-3 > leptin > IGF-1.
doi:10.1158/1940-6207.CAPR-11-0454
PMCID: PMC3294132  PMID: 22246620
physical activity; dietary energy restriction; mammary carcinogenesis; adipokines; insulin like growth factors; chronic inflammation
2.  Effect of dietary patterns differing in carbohydrate and fat content on blood lipid and glucose profiles based on weight-loss success of breast-cancer survivors 
Introduction
Healthy body weight is an important factor for prevention of breast cancer recurrence. Yet, weight loss and weight gain are not currently included in clinical-practice guidelines for posttreatment of breast cancer. The work reported addresses one of the questions that must be considered in recommending weight loss to patients: does it matter what diet plan is used, a question of particular importance because breast cancer treatment can increase risk for cardiovascular disease.
Methods
Women who completed treatment for breast cancer were enrolled in a nonrandomized, controlled study investigating effects of weight loss achieved by using two dietary patterns at the extremes of macronutrient composition, although both diet arms were equivalent in protein: high fat, low carbohydrate versus low fat, high carbohydrate. A nonintervention group served as the control arm; women were assigned to intervention arms based on dietary preferences. During the 6-month weight-loss program, which was menu and recipe defined, participants had monthly clinical visits at which anthropometric data were collected and fasting blood was obtained for safety monitoring for plasma lipid profiles and fasting glucose. Results from 142 participants are reported.
Results
Adverse effects on fasting blood lipids or glucose were not observed in either dietary arm. A decrease in fasting glucose was observed with progressive weight loss and was greater in participants who lost more weight, but the effect was not statistically significant, even though it was observed across both diet groups (P = 0.21). Beneficial effects of weight loss on cholesterol (4.7%; P = 0.001), triglycerides (21.8%; P = 0.01), and low-density lipoprotein (LDL) cholesterol (5.8%; P = 0.06) were observed in both groups. For cholesterol (P = 0.07) and LDL cholesterol (P = 0.13), greater reduction trends were seen on the low-fat diet pattern; whereas, for triglycerides (P = 0.01) and high-density lipoprotein (HDL) cholesterol (P = 0.08), a decrease or increase, respectively, was greater on the low-carbohydrate diet pattern.
Conclusions
Because an individual's dietary preferences can affect dietary adherence and weight-loss success, the lack of evidence of a negative effect of dietary pattern on biomarkers associated with cardiovascular risk is an important consideration in the development of breast cancer practice guidelines for physicians who recommend that their patients lose weight. Whether dietary pattern affects biomarkers that predict long-term survival is a primary question in this ongoing clinical trial.
doi:10.1186/bcr3082
PMCID: PMC3496116  PMID: 22225711
3.  Metformin as an energy restriction mimetic agent for breast cancer prevention 
Background:
This study examined whether metformin administration inhibited chemically induced mammary carcinogenesis in rats. In cancer prevention, metformin may act (1) indirectly through reducing systemic risk factors; or (2) directly through AMPK-mediated signaling. To begin to delineate clinically relevant mechanisms for breast cancer prevention, metformin was also studied along with dietary energy restriction.
Materials and Methods:
Mammary cancer was induced in female Sprague--Dawley rats (50 mg/kg MNU, i.p.). Metformin was fed alone (AIN93G + 0.05 to 1.0% w/w metformin) or combined with 40% dietary energy restriction. Plasma analytes (e.g., insulin, glucose, IGF-1) and protein expression (e.g., AMPK, mTOR, Akt) in mammary carcinomas and liver were evaluated. Additional studies included (1) aldehyde dehydrogenase flow cytometry, to gauge potential for cancer-initiated cells in mammary carcinomas to respond to metformin; (2) cell culture, to understand dose response (0.02--20 mM) of different cancer cell line molecular subtypes to metformin; and (3) analysis of a rat mammary epithelial cell microarray database, to examine expression of genes related to metformin pharmacokinetics (e.g., organic cation transporters) and pharmacodynamics (e.g., complex I of electron transport).
Results:
While a dosing regimen of 1.0%/0.25% metformin-reduced palpable mammary carcinoma incidence, multiplicity, and tumor burden and prolonged latency, lower doses of metformin failed to inhibit carcinogenesis despite effects on plasma insulin. Human breast cancer cell growth inhibition in response to metformin was only observed at high concentrations. Poor in vivo and in vitro response to metformin may be the result of pharmacokinetic (OCT-1 expression was low in rat mammary cells; OCT-3 was downregulated in mammary carcinoma) and pharmacodynamic (complex I transcripts were higher in mammary epithelial cells from carcinomas versus uninvolved gland) effects. In combination with dietary energy restriction, metformin offered protection against new tumor occurrence following release from combined treatment. Flow cytometry indicated the presence of cancer-initiated cells in mammary carcinomas.
Conclusions:
As a single agent, metformin possessed limited cancer inhibitory activity. However, metformin may be an effective component of multiagent interventions that target cancer-initiated cells. There is a clear need to identify the conditions under which metformin is likely to benefit prevention and control of breast cancer.
PMCID: PMC3142764  PMID: 21799661
AMP-activated protein kinase; insulin; mammalian target of rapamycin; mammary carcinogenesis; metformin
4.  Effect of a low fat versus a low carbohydrate weight loss dietary intervention on biomarkers of long term survival in breast cancer patients ('CHOICE'): study protocol 
BMC Cancer  2011;11:287.
Background
Weight loss in overweight or obese breast cancer patients is associated with an improved prognosis for long term survival. However, it is not clear whether the macronutrient composition of the chosen weight loss dietary plan imparts further prognostic benefit. A study protocol is presented for a dietary intervention to investigate the effects of weight loss dietary patterns that vary markedly in fat and carbohydrate contents on biomarkers of exposure to metabolic processes that may promote tumorigenesis and that are predictive of long term survival. The study will also determine how much weight must be lost for biomarkers to change in a favorable direction.
Methods/Design
Approximately 370 overweight or obese postmenopausal breast cancer survivors (body mass index: 25.0 to 34.9 kg/m2) will be accrued and assigned to one of two weight loss intervention programs or a non-intervention control group. The dietary intervention is implemented in a free living population to test the two extremes of popular weight loss dietary patterns: a high carbohydrate, low fat diet versus a low carbohydrate, high fat diet. The effects of these dietary patterns on biomarkers for glucose homeostasis, chronic inflammation, cellular oxidation, and steroid sex hormone metabolism will be measured. Participants will attend 3 screening and dietary education visits, and 7 monthly one-on-one dietary counseling and clinical data measurement visits in addition to 5 group visits in the intervention arms. Participants in the control arm will attend two clinical data measurement visits at baseline and 6 months. The primary outcome is high sensitivity C-reactive protein. Secondary outcomes include interleukin-6, tumor necrosis factor-α, insulin-like growth factor-1 (IGF), IGF binding protein-3, 8-isoprostane-F2-alpha, estrone, estradiol, progesterone, sex hormone binding globulin, adiponectin, and leptin.
Discussion
While clinical data indicate that excess weight for height is associated with poor prognosis for long term survival, little attention is paid to weight control in the clinical management of breast cancer. This study will provide information that can be used to answer important patient questions about the effects of dietary pattern and magnitude of weight loss on long term survival following breast cancer treatment.
Clinical Trial Registration
CA125243
doi:10.1186/1471-2407-11-287
PMCID: PMC3150342  PMID: 21733177
biomarkers; dietary patterns; low fat; low carbohydrate; weight loss; breast cancer; long term survival
5.  Quantitative Assessment of Mammary Gland Density in Rodents Using Digital Image Analysis 
Background
Rodent models have been used extensively to study mammary gland development and for studies of toxicology and carcinogenesis. Mammary gland gross morphology can visualized via the excision of intact mammary gland chains following fixation and staining with carmine using a tissue preparation referred to as a whole mount. Methods are described for the automated collection of digital images from an entire mammary gland whole mount and for the interrogation of digital data using a "masking" technique available with Image-Pro® plus image analysis software (Mediacybernetics. Silver Spring, MD).
Results
Parallel to mammographic analysis in humans, measurements of rodent mammary gland density were derived from area-based or volume-based algorithms and included: total circumscribed mammary fat pad mass, mammary epithelial mass, and epithelium-free fat pad mass. These values permitted estimation of absolute mass of mammary epithelium as well as breast density. The biological plausibility of these measurements was evaluated in mammary whole mounts from rats and mice. During mammary gland development, absolute epithelial mass increased linearly without significant changes in mammographic density. Treatment of rodents with tamoxifen, 9-cis-retinoic acid, or ovariectomy, and occurrence of diet induced obesity decreased both absolute epithelial mass and mammographic density. The area and volumetric methods gave similar results.
Conclusions
Digital image analysis can be used for screening agents for potential impact on reproductive toxicity or carcinogenesis as well as for mechanistic studies, particularly for cumulative effects on mammary epithelial mass as well as translational studies of mechanisms that explain the relationship between epithelial mass and cancer risk.
doi:10.1186/1480-9222-13-4
PMCID: PMC3129309  PMID: 21663682
6.  A Method for Serial Tissue Processing and Parallel Analysis of Aberrant Crypt Morphology, Mucin Depletion, and Beta-Catenin Staining in an Experimental Model of Colon Carcinogenesis 
Biological Procedures Online  2010;12:118-130.
The use of architectural and morphological characteristics of cells for establishing prognostic indicators by which individual pathologies are assigned grade and stage is a well-accepted practice. Advances in automated micro- and macroscopic image acquisition and digital image analysis have created new opportunities in the field of prognostic assessment; but, one area in experimental pathology, animal models for colon cancer, has not taken advantage of these opportunities. This situation is primarily due to the methods available to evaluate the colon of the rodent for the presence of premalignant and malignant pathologies. We report a new method for the excision and processing of the entire colon of the rat and illustrate how this procedure permitted the quantitative assessment of aberrant crypt foci (ACF), a premalignant colon pathology, for characteristics consistent with progression to malignancy. ACF were detected by methylene blue staining and subjected to quantitative morphometric analysis. Colons were then restained with high iron diamine–alcian blue for assessment of mucin depletion using an image overlay to associate morphometric data with mucin depletion. The subsequent evaluation of ACF for beta-catenin staining is also demonstrated. The methods described are particularly relevant to the screening of compounds for cancer chemopreventive activity.
doi:10.1007/s12575-010-9032-x
PMCID: PMC3284111  PMID: 21406072
colon carcinogenesis; aberrant crypt foci; mucin depletion; beta-catenin; image analysis; morphometry
7.  Collection of Epithelial Cells from Rodent Mammary Gland Via Laser Capture Microdissection Yielding High-Quality RNA Suitable for Microarray Analysis 
Laser capture microdissection (LCM) enables collection of cell populations highly enriched for specific cell types that have the potential of yielding critical information about physiological and pathophysiological processes. One use of cells collected by LCM is for gene expression profiling. Samples intended for transcript analyses should be of the highest quality possible. RNA degradation is an ever-present concern in molecular biological assays, and LCM is no exception. This paper identifies issues related to preparation, collection, and processing in a lipid-rich tissue, rodent mammary gland, in which the epithelial to stromal cell ratio is low and the stromal component is primarily adipocytes, a situation that presents numerous technical challenges for high-quality RNA isolation. Our goal was to improve the procedure so that a greater probe set present call rate would be obtained when isolated RNA was evaluated using Affymetrix microarrays. The results showed that the quality of RNA isolated from epithelial cells of both mammary gland and mammary adenocarcinomas was high with a probe set present call rate of 65% and a high signal-to-noise ratio.
doi:10.1007/s12575-010-9026-8
PMCID: PMC3055717  PMID: 21406068
Laser capture microdissection; Mammary epithelial cells; RNA quality
8.  Effect of Nonmotorized Wheel Running on Mammary Carcinogenesis: Circulating Biomarkers, Cellular Processes, and Molecular Mechanisms in Rats 
The objective of this experiment was to identify circulating growth factors, hormones, and cellular and molecular mechanisms that account for the effects of physical activity on mammary carcinogenesis. A total of 120 female Sprague-Dawley rats were injected with 1-methyl-1-nitrosourea (50 mg/kg) and 7 days thereafter were randomized to either a physically active or a sedentary control group. Individually housed rats were given free access to a nonmotorized, computer-controlled activity wheel and running behavior was reinforced by food reward. Rats self-determined their daily intensity and duration of running. Sedentary control rats received the same amount of food as the physically active rats to which they were paired. Physical activity reduced mammary cancer incidence (P = 0.015) and cancer multiplicity (P = 0.01). Physical activity induced changes in plasma insulin, insulin-like growth factor-I, and corticosterone, suggesting that mechanisms regulating glucose homeostasis were affected. Western blot analyses of mammary carcinomas revealed that proteins involved in cell proliferation were reduced (P < 0.001) and those involved in apoptosis via the mitochondrial pathway were elevated (P < 0.001) by physical activity. The hypothesis that these effects were mediated by activation of AMP-activated protein kinase, and down-regulation of protein kinase B, which collectively down-regulate the activity of the mammalian target of rapamycin, was evaluated. Evidence in support of this hypothesis was found in the Western blot analyses of mammary carcinomas, mammary gland, liver, and skeletal muscle. Collectively, these findings provide a rationale for additional studies of energy-sensing pathways in the elucidation of mechanisms that account for the inhibition of carcinogenesis by physical activity.
doi:10.1158/1055-9965.EPI-08-0175
PMCID: PMC2667869  PMID: 18708381

Results 1-8 (8)