Preclinical Breast Cancer Models to Investigate Metabolic Priming by Methionine Restriction
We have developed a novel therapeutic paradigm (“metabolic priming”) for cancer whereby restriction of the essential amino acid methionine activates a number of cell-stress-response pathways that can be selectively targeted to enhance the therapeutic impact of methionine restriction. One example of metabolic priming is the combination of methionine restriction with proapoptotic TRAIL receptor-2 (TRAIL-R2) agonists. Methionine restriction enhances the cell surface expression of TRAIL-R2 selectively in transformed breast epithelial cells and renders them more susceptible to cell death induction by TRAIL-R2 agonists in cellular and murine models of breast cancer. This methods review focuses on preclinical models of breast cancer to investigate metabolic priming by methionine restriction. Multiple cell-based methods are detailed to measure cell viability, cell survival, caspase activity, apoptosis, and matrix detachment-induced cell death (anoikis). In addition, we describe an orthotopic model of metastatic breast cancer that utilizes mCherry-fluorescently-labeled human breast cancer cells. This model captures the entire metastatic cascade from the mammary gland to the lung and mimics key features of the human disease. These breast-cancer models can be readily adapted to other tumor types. Overall, we provide a stepwise, translationally-relevant approach to study metabolic priming in the context of cancer.
Key wordsMethionine Metabolism TRAIL Breast cancer Metastasis Apoptosis Therapeutics Murine models
We are indebted to Robin Humphreys for providing agonistic TRAIL receptor mAbs. This work was supported by grants from the V Foundation for Cancer Research, Breast Cancer Research Foundation, Avon Breast Cancer Crusade, UW Carbone Cancer Center pilot funding, and the Wisconsin Partnership Program.
- 15.Trarbach T, Moehler M, Heinemann V, Kohne CH, Przyborek M, Schulz C et al (2010) Phase II trial of mapatumumab, a fully human agonistic monoclonal antibody that targets and activates the tumour necrosis factor apoptosis-inducing ligand receptor-1 (TRAIL-R1), in patients with refractory colorectal cancer. Br J Cancer 102:506–512CrossRefGoogle Scholar