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

Authors' Affiliations: ¹ Breast Biology Group, School of Cancer and Imaging Sciences, Paterson Institute for Cancer Research, University of Manchester; ² Genesis Breast Cancer Prevention and Nightingale Centres, University Hospital of South Manchester NHS Trust; ³ Manchester Centre for Integrative Systems Biology and ⁴ School of Chemistry, The Manchester Interdisciplinary Biocentre, The University of Manchester; ⁵ Breakthrough Breast Cancer Research Unit, Paterson Institute for Cancer Research, Manchester, United Kingdom

Requests for reprints: Robert B. Clarke, Breast Biology Group, School of Cancer and Imaging Sciences, Paterson Institute for Cancer Research, University of Manchester, Wilmslow Road, Manchester M20 4BX, United Kingdom. Phone: 44-1614463210; Fax: 44-1614463109; E-mail: rclarke{at}picr.man.ac.uk or Anthony Howell, Breakthrough Breast Cancer Research Unit, Paterson Institute for Cancer Research, Wilmslow Road, Manchester M20 4BX, United Kingdom. E-mail: Maria.parker{at}christie.nhs.uk.

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 down-regulated.

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.

Key Words: biomarkers • diet • energy restriction • adipose • breast • obesity • gene expression • metabolomics