Biomarkers of Dietary Energy Restriction in Women at Increased Risk of Breast Cancer

Abstract

Dietary energy restriction (DER) reduces risk of spontaneous mammary cancer in rodents. In humans, DER in premenopausal years seems to reduce risk of postmenopausal breast cancer. Markers of DER are required to develop acceptable DER regimens for breast cancer prevention. We therefore examined markers of DER in the breast, adipose tissue, and serum.Nineteen overweight or obese women at moderately increased risk of breast cancer (lifetime risk, 1 in 6 to 1 in 3) ages between 35 and 45 were randomly allocated to DER [liquid diet, 3,656 kJ/d (864 kcal/d); n = 10] or asked to continue their normal eating patterns (n = 9) for one menstrual cycle. Biopsies of the breast and abdominal fat were taken before and after the intervention. RNA was extracted from whole tissues and breast epithelium (by laser capture microdissection) and hybridized to Affymetrix GeneChips. Longitudinal plasma and urine samples were collected before and after intervention, and metabolic profiles were generated using gas chromatography-mass spectrometry.DER was associated with significant reductions in weight [−7.0 (±2.3) kg] and in alterations of serum biomarkers of breast cancer risk (insulin, leptin, total and low-density lipoprotein cholesterol, and triglycerides). In both abdominal and breast tissues, as well as isolated breast epithelial cells, genes involved in glycolytic and lipid synthesis pathways (including stearoyl-CoA desaturase, fatty acid desaturase, and aldolase C) were significantly downregulated.We conclude that reduced expressions of genes in the lipid metabolism and glycolytic pathways are detectable in breast tissue following DER, and these may represent targets for DER mimetics as effective chemoprophylactic agents.Dietary energy restriction (DER) significantly reduces spontaneous mammary tumors in laboratory rodents irrespective of the type of macronutrient restricted (1). Observational studies indicate that weight loss in premenopausal or postmenopausal women reduces the risk of postmenopausal breast cancer (2, 3). For example, in the Iowa Women's Health Study, women who lost >5% of their body weight before menopause had 40% fewer breast cancers in the postmenopausal period compared with women who continued to gain weight (2). Postmenopausal weight loss of >10 kg reduced postmenopausal breast cancer by 60% in the Nurses' Health Study, and >5% postmenopausal weight loss in the Iowa Women's Health Study was associated with a 25% reduction in risk (2, 3). Reduction in cancer risk is also seen after weight reduction after bariatric surgery (4-7). DER is associated with diverse cellular changes, including alteration of growth factor, signaling and metabolic pathways, and reduction of cell proliferation (8, 9), in animal studies. DER favorably alters serum markers of breast cancer risk, such as insulin, leptin, sex hormone binding globulin (SHBG), and lipids, in women who are overweight or

Resveratrol Supplementation Does Not Improve Metabolic Function in Nonobese Women with Normal Glucose Tolerance

“…In contrast, we found moderate weight loss induced significant changes in gene expression profiles in adipose tissue and skeletal muscle, particularly genes that are known as CR targets in adipose tissue, identified in previous microarray studies conducted in human subjects (Capel et al, 2008; Johansson et al, 2012; Kolehmainen et al, 2008; Ong et al, 2009; Viguerie et al, 2005). However, data from several studies conducted in rodent models have found many putative resveratrol targets, such as Sirt1, Nampt, and Pgc-1α , are affected by fasting (Hayashida et al, 2010; Yang et al, 2007; Yoon et al, 2001), so it is possible that collecting tissue samples from our subjects after they fasted overnight (~12 h) masked an effect induced by resveratrol on tissue gene expression.…”

“…Nonetheless, CR-induced moderate weight loss altered adipose tissue gene expression profiles in several CR targets identified previously in human subjects, including up-regulation of Ctep (Johansson et al, 2012) and down-regulation of Leptin (Viguerie et al, 2005), Aldoc (Capel et al, 2008; Johansson et al, 2012; Ong et al, 2009), Abcc6 (Ong et al, 2009), and Ccnd2 (Kolehmainen et al, 2008) (Figure S1). …”

Favorable effects of low-fat and low-carbohydrate dietary patterns on serum leptin, but not adiponectin, among overweight and obese premenopausal women: a randomized trial

“…Several dietary trials have evaluated the effects of LFD and/or LCD interventions on adipokine concentrations (de Luis et al 2007; Bluher et al 2012; Befort et al 2012; Scott et al 2013; Giannopoulou et al 2005; Friedenreich et al 2011; Sacks et al 2009; Davis et al 2009; Foster et al 2003; Samaha et al 2003; Brehm et al 2003; Yancy et al 2004; Shai et al 2008; Bradley et al 2009; Reed et al 2010; Ata et al 2010; Ong et al 2009; Harvie et al 2011), but few have focused on premenopausal women (Reed et al 2010; Ata et al 2010; Ong et al 2009; Harvie et al 2011). In our study, overweight and obese premenopausal women were randomized to a LFD or a LCD plus PA for a period of 52 weeks.…”

“…A recent study (Harvie et al 2011) examined the effects of a 6-month trial of intermittent and continuous calorie-restricted diets without exercise among premenopausal women and found that these diets yielded significant reduced leptin (approximately 40%) and increased the A/L ratio (approximately 20%). Another study (Ong et al 2009) examined the effects of a 1-month calorie-restricted intervention (62% carbohydrates, 26% protein, and 12% fat), without exercise, on adipokine concentrations and adipokine expression profiles among overweight and obese premenopausal women. They found that post-intervention adiponectin and leptin concentrations were 3% and 60% lower, respectively (Ong et al 2009).…”

A Low-Glycemic Load Diet Reduces Serum C-Reactive Protein and Modestly Increases Adiponectin in Overweight and Obese Adults4

“…The Carbohydrates and Related Biomarkers Study was a randomized, cross-over, feeding study testing the effect of low-and high-GL diets on chronic disease susceptibility biomarkers, including biomarkers of inflammation and adipokines, which have been associated with increased risk of cancer, cardiovascular disease, and other chronic diseases (1,(28)(29)(30). The Carbohydrates and Related Biomarkers Study was conducted between June 2006 and July 2009.…”