Abstract
BackgroundObservational studies suggest weight loss and energy restriction reduce breast cancer risk. Intermittent energy restriction (IER) reduces weight to the same extent as, or more than equivalent continuous energy restriction (CER) but the effects of IER on normal breast tissue and systemic metabolism as indicators of breast cancer risk are unknown.MethodsWe assessed the effect of IER (two days of 65 % energy restriction per week) for one menstrual cycle on breast tissue gene expression using Affymetrix GeneChips, adipocyte size by morphometry, and systemic metabolism (insulin resistance, lipids, serum and urine metabolites, lymphocyte gene expression) in 23 overweight premenopausal women at high risk of breast cancer. Unsupervised and supervised analyses of matched pre and post IER biopsies in 20 subjects were performed, whilst liquid and gas chromatography mass spectrometry assessed corresponding changes in serum and urine metabolites in all subjects after the two restricted and five unrestricted days of the IER.ResultsWomen lost 4.8 % (±2.0 %) of body weight and 8.0 % (±5.0 %) of total body fat. Insulin resistance (homeostatic model assessment (HOMA)) reduced by 29.8 % (±17.8 %) on the restricted days and by 11 % (±34 %) on the unrestricted days of the IER. Five hundred and twenty-seven metabolites significantly increased or decreased during the two restricted days of IER. Ninety-one percent of these returned to baseline after 5 days of normal eating. Eleven subjects (55 %) displayed reductions in energy restriction-associated metabolic gene pathways including lipid synthesis, gluconeogenesis and glycogen synthesis. Some of these women also had increases in genes associated with breast epithelial cell differentiation (secretoglobulins, milk proteins and mucins) and decreased collagen synthesis (TNMD, PCOLCE2, TIMP4). There was no appreciable effect of IER on breast gene expression in the other nine subjects. These groups did not differ in the degree of changes in weight, total body fat, fat cell size or serum or urine metabolomic markers. Corresponding gene changes were not seen in peripheral blood lymphocytes.ConclusionThe transcriptional response to IER is variable in breast tissue, which was not reflected in the systemic response, which occurred in all subjects. The mechanisms of breast responsiveness/non-responsiveness require further investigation.Trial registrationISRCTN77916487 31/07/2012.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-016-0714-4) contains supplementary material, which is available to authorized users.
Highlights
Observational studies suggest weight loss and energy restriction reduce breast cancer risk
We demonstrated that intermittent energy restriction (IER), which involves strict 65 % energy restriction for two days and normal healthy eating with a Mediterranean diet for five days each week is achievable and is associated with reduction in weight, body fat [10] and insulin resistance [10, 11] amongst overweight/obese women
Overall we found that Intermittent energy restriction (IER) induces more subtle and variable changes on breast gene expression than continuous energy restriction (CER)
Summary
Observational studies suggest weight loss and energy restriction reduce breast cancer risk. Intermittent energy restriction (IER) reduces weight to the same extent as, or more than equivalent continuous energy restriction (CER) but the effects of IER on normal breast tissue and systemic metabolism as indicators of breast cancer risk are unknown. Observational studies in women indicate that weight gain increases breast cancer risk and weight reduction decreases breast cancer risk [1,2,3,4]. In the Iowa Women’s Health Study, ≥5 % maintained weight loss resulted in 20–40 % reduction in postmenopausal breast cancer risk compared with women who continued to gain weight [1]. Multiple studies in rodent models indicate that energy restriction reduces the risk of breast cancer [5] This effect appears to be mediated by changes in a number of systemic factors and local factors within breast cells. Poor adherence to continuous energy restriction (CER) means energy restriction is difficult to implement
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