Breast Cancer Secreted Factors Alter The Bone Microenvironment

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Potential New Targets for Bone Metastasis Treatment

Valerie A. Siclari, Theresa A. Guise, and John M. Chirgwin

Division of Endocrinology, University of Virginia, PO Box 801401, Charlottesville, VA 22908-1401, USA

Abstract: Bone is the most common site of breast cancer metastasis. Over eighty percent of patients with advanced breast cancer develop bone metastases. Once breast cancer has spread to bone, the cancer is incurable and patients develop mostly osteolytic, but also osteoblastic, or mixed bone lesions and suffer from extreme bone pain, skeletal fractures, hypercalcemia, and nerve compression. Current treatment is the use of antiresorptive bisphos-phonates, which reduces bone pain and skeletal fractures but does not improve overall survival. Mouse models of bone metastasis have led to an understanding of the complex interactions that occur within bone that contribute to the incurability of the disease. Once breast cancer cells enter bone, a "vicious cycle" develops between breast cancer cells and the other cells within bone. Breast cancer cells secrete factors that stimulate bone cells, causing them in turn to secrete factors back onto the cancer cells. Inhibiting the actions of cancer-secreted factors may break this vicious cycle. The list of tumor-secreted factors is long, but they can be divided into three groups: (1) bone-resorbing, (2) bone-forming, and (3) metastasis-opposing factors. These factors may share upstream regulatory pathways. Such central pathways could provide new targets for more effective treatment of bone metastasis. The TGFp and hypoxia-induced Hifla pathways are two leading targets for such adjuvant treatments.

Keywords: breast cancer, bone metastasis, tumor-secreted factors

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