The role of effective energy restriction on metastatic tumor growth
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Obesity is a modifiable lifestyle factor known to exacerbate breast cancer risk, progression, and mortality. Conversely, energy restriction and weight loss are associated with a decreased breast cancer risk in women, and inhibit mammary tumor growth and metastasis in multiple tumor models. Although continuous energy restriction (CER) is the standard approach to weight loss, it is associated with poor patient adherence. Intermittent energy restriction (IER) is a dietary regimen whereby periods of energy restriction are interspersed with periods of normal food intake. IER is as effective or even superior to CER in achieving weight loss, and enjoys a higher level of patient compliance, rendering IER a promising lifestyle intervention. The epithelialmesenchymal transition (EMT) plays important roles in breast cancer invasion and metastasis. The induction of EMT elicits the conversion of sessile epithelial carcinoma cells into intrinsically motile mesenchymal counterparts, and bestows cancer stem cell (CSC) traits. EMT is accompanied by extensive metabolic reprogramming including enhanced aerobic glycolysis and increased expression of glycolytic pathway components. Recent evidence suggests that the EMTinducing transcription factors TWIST and SLUG promote both EMT and aerobic glycolysis. Here, we hypothesize that EMT may be regulated by energy balance, and that energy restriction may be leveraged to inhibit EMT and curtail breast cancer progression. We aim to investigate the effects of IER on cell differentiation, EMT, and metastasis in triple negative breast cancers (TNBCs), which are enriched for EMT features. MDAMB231IER and SUM159IER TNBC cells, cultured under an IER regimen, exhibited an epitheliallike phenotype, and decreased invasiveness and migratory potential, compared with controls. Immunoblotting and immunofluorescence showed decreased protein levels of TWIST and SLUG in IERtreated cells, compared with controls, while mRNA levels were unchanged. IERtreated cells also exhibited decreased expression of the CSCassociated cell surface marker, CD44, and a markedly reduced mammosphereforming efficiency, indicative of diminished selfrenewal capacity. Accordingly, tumor formation was compromised in mice injected with MDA231IER cells relative to controls. IERtreated cells displayed intense punctate staining for the autophagosome marker LC3II suggesting that IER may stimulate autophagymediated TWIST and SLUG degradation. We are currently evaluating the impact of the IER regimen on the metastatic potential of TNBC cells and their response to standardofcare drugs, and investigating the molecular mechanisms underpinning the inhibition of EMT by IER. Understanding how to leverage IER to curtail cancer progression, and identifying the molecular mechanisms underlying IERdependent cancer preventive effects may lead to novel drugs and intervention strategies for the prevention and treatment of metastatic breast cancers, including TNBCs.Support or Funding InformationNIHThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
