Abstract
Purpose
Obesity and weight gain are associated with comorbidities including a higher risk of tumor recurrence and cancer-related deaths among breast cancer (BC) survivors; however, the underlying mechanisms linking obesity and cancer are poorly understood. Given the lack of clinically validated BC biomarkers, obesity and weight-loss studies utilize serum biomarkers as the intermediary outcomes of tumor recurrence. Studies have indicated microRNAs (miRNA)s are reliable biomarkers for cancer. We hypothesized that miRNA expression correlates with obesity and weight loss amongst BC survivors. This would yield insight into the biological pathways by which this association occurs, enabling more precise development of therapeutics.
Patients and methods
We correlated baseline body mass index (BMI) with serum miRNA expression in 121 BC survivors enrolled in the Hormones and Physical Exercise (HOPE) trial. We then analyzed expression of the 35 most abundant miRNAs from HOPE in a six-month randomized controlled weight-loss trial (Lifestyle, Exercise, and Nutrition; LEAN) in 100 BC survivors. Ingenuity pathway analysis (IPA) software was used to identify biological pathway targets of the BMI-associated and intervention-responsive miRNAs using predictive biomarkers.
Results
Pearson correlations in HOPE identified eight miRNAs associated with BMI, including miR-191-5p (r = − 0.22, p = 0.016) and miR-122-5p (r = 0.25, p = 0.0048). In the LEAN validation study, levels of miR-191-5p significantly increased during the six-month intervention (p = 0.082). Ingenuity Pathway Analysis identified “Estrogen-mediated S-phase entry” (HOPE p = 0.003; LEAN p < 0.001) and “Molecular mechanisms of cancer” (HOPE p = 0.02; LEAN p < 0.001) as the top canonical pathways that significantly correlated with BMI-associated and intervention-responsive miRNAs and contain obesity and cancer-relevant genes including the E2F family of transcription factors and CCND1, which have been implicated in sporadic BC.
Conclusion
While the association between obesity and BC recurrence and mortality has been demonstrated in the literature, mechanisms underlying the link between weight gain and cancer are unclear. Using two independent clinical trials, we identified novel miRNAs associative to BMI and weight loss that contribute to the development of cancer. Predictive modeling of miRNA targets identified multiple canonical pathways associated with cancer, highlighting potential mechanisms explaining the link between BMI and increased cancer risk.
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Acknowledgements
This work was supported by grants to B.D. Adams from NIH P50 CA196530, a Firefly Pilot Grant award, and from start-up funds through The RNA Institute, and The State University of New York. B.D. Adams is also President and CEO of The Brain Institute of America (brian.adams@braininstitueamerica.com) and holds patent interests with AUM LifeTech. B. Cartmel is a consultant/advisor for Pfizer. F. Li is supported by Yale CTSA grant UL1TR000142, and Yale Cancer Center Support Grant(CCSG/P30). M. Harrigan and T. Sanft are supported by grant NIH 1R01CA207753-01A1. T. Sanft is also a consultant/advisor to bioTheranostics. C.J. Cheng is currently an employee of Alexion Pharmaceuticals. L. Pusztai is supported by a Breast Cancer Research Foundation Award. M.L. Irwin is supported by grants from NCI R01CA132931, the American Institute for Cancer Research, and by the Breast Cancer Research Foundation, as well as through a Yale Cancer Center Support Grant P30CA016359, and a Clinical and Translational Science Award NCATS UL1TR000142. We thank Jessica Tytell, Irene G. Reed, and Elizabeth Posey for the critical reading of this manuscript. We thank Mike Tackett at Firefly for answering questions regarding miRNA detection within serum samples. Other authors have declared that no conflict of interest exists. This study analyzed data obtained from clinical trials NCT02056067 and NCT02109068.
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Conception and design: Brian D. Adams, Melinda L. Irwin. Financial support: Brian D. Adams, Melinda L. Irwin. Provision of study materials or patients: Melinda L. Irwin. Collection and assembly of data: Brian D. Adams, Monica J. Hubal, Melinda L. Irwin. Data analysis and interpretation: all authors. Manuscript writing: all authors
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B.D. Adams is President and CEO of The Brain Institute of America and holds patent interests with AUM LifeTech. Other authors have declared no conflicts of interest exist.
Clinical trial
This study analyzed data obtained from clinical trials Hormones and Physical Exercise (HOPE) Study; NCT02056067, https://clinicaltrials.gov/ct2/show/NCT02056067; and Lifestyle, Exercise and Nutrition (LEAN) Study; NCT02109068, https://clinicaltrials.gov/ct2/show/NCT02109068.
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Adams, B.D., Arem, H., Hubal, M.J. et al. Exercise and weight loss interventions and miRNA expression in women with breast cancer. Breast Cancer Res Treat 170, 55–67 (2018). https://doi.org/10.1007/s10549-018-4738-6
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DOI: https://doi.org/10.1007/s10549-018-4738-6