Project Summary/Abstract Treatment of early stage breast cancer has substantially improved but preventing metastasis remains a more elusive target. Obesity, which is endemic in our society, is associated with an increased risk of breast cancer and accelerated metastasis. The means by which obesity compromises survival of breast cancer patients is, however, poorly understood. Liver is among the most common sites of breast cancer metastasis and its occurrence is generally associated with poor prognosis. Liver health is closely related to weight as obesity is the major cause of fatty liver disease, estimated to be present in 1/4 to 1/3 of Americans. We discovered that fatty liver disease markedly increases liver metastasis, in mice, by providing fuel to tumor cells thereby accelerating their growth. Examination of human liver biopsies and MRI analysis suggests the same is true in women with metastatic breast cancer. Thus, our first goal is to determine if treating fatty liver disease reduces breast cancer liver metastasis and improves its response to chemotherapy. To identify potential new treatments for liver metastasis we will explore the mechanisms by which fatty liver disease stimulates tumor growth. Finally, we will ask if human breast cancers exhibit the same liver metastatic properties as those arising in mice. If our conclusion proves true, treatment of breast cancer will universally require prevention and treatment of fatty liver disease and therefore impact all affected women. Prevention and treatment of fatty liver disease in breast cancer patients, however, may likely reduce liver metastasis and therefore prolong survival. Because fatty liver disease is most often the product of obesity, educating patients about calorie intake, which can be instituted immediately, may have significant effects on breast cancer prognosis.