US EPA

2145235 

Technical Report 

Does Skeletal Muscle Mass Influence Breast Cancer. Evaluating Mammary Tumorigenesis and Progression in Genetically Hyper-Muscular Mice 

Zimmers, T 

2007 

NTIS/00370010_a 

GRA and I 

GRA and I 

Epidemiologic evidence demonstrates that caloric restriction and physical activity independently reduce breast cancer, potentially by decreasing adiposity and insulin resistance. To determine the role of increased skeletal muscle mass on breast cancer, the authors sought to measure rates of chemically induced mammary tumorigenesis and progression in genetically hypermuscular mice, including mice lacking the muscle growth inhibitor myostatin and mice expressing a dominant negative form of the myostatin receptor (MLC-dnActRIIB mice). Mammary cancer was induced by a combination of a tumor promoter, medroxyprogesterone acetate (MPA), and a carcinogen, dimethylbenz-a-anthracene (DMBA). Technical difficulties with the model required them to seek a no-cost extension for one year. Further experience indicated that body composition of the mice affected the pharmacodynamics of drug administration (i.e., MPA and DMBA given in ethanol and oil had different bioavailability in lean, hypermuscular mice versus mice of normal body type, confounding interpretation of the results). Now the authors have switched to a genetic model of mammary cancer which they are breeding into their hypermuscular mice and the results are pending. In the interim, they used genetic and pharmacological inhibition of the myostatin pathway to potentially preserve muscle in the end-stages of cancer, cancer cachexia. Up to 25% of breast cancer deaths may be attributed to muscle wasting from the complex metabolic syndrome induced by the tumor. However, despite increasing normal muscle growth, myostatin inhibition failed to protect mice from cancer cachexia.