Molecular interactions between breast cancer cells and the bone microenvironment drive skeletal metastases V.A. Siclari & T.A. Guise & J.M. Chirgwin Published online: 13 December 2006 # Springer Science + Business Media, LLC 2006 Abstract Breast cancer cells preferentially spread to bone. Bone metastases are currently incurable and therefore better treatments need to be developed. Metastasis is an ineffi- cient, multi-step process. Specific aspects of both breast cancer cells and the bone microenvironment contribute to the development of bone metastases. Breast cancers express chemokine receptors, integrins, cadherins, and bone-resorb- ing and bone-forming factors that contribute to the successful and preferential spread of tumor to bone. Bone is rich in growth factors and cell types that make it a hospitable environment for breast cancer growth. Once breast cancer cells enter the bone, a highly complex vicious cycle develops, in which breast cancer cells secrete factors that act on bone cells and other cells within the bone (stem cells, T cells, platelets, adipocytes, fibroblasts, and endo- thelial cells), causing them to secrete factors that act on adjacent cancer cells. The steps in the metastatic cascade and the vicious cycle within bone offer unique targets for adjuvant treatments to treat and cure bone metastases. Keywords Breast cancer . Bone metastasis . Bone microenvironment 1 Introduction Breast cancer is one of several cancers including lung and prostate cancer that preferentially spreads to bone [1]. One out of every eight women will develop breast cancer during her lifetime (http://www.cancer.org/cancerinfo). Of those women who progress to an advanced stage of disease, over 80% will develop bone metastases [2]. Cancer cells enter bone through nutrient arteries and typically form metastases in the axial skeleton. In particular, they form in the vertebrae, pelvis, the proximal ends of the long bones, and the skull [3, 4]. Within bone, the breast cancer cells produce osteolytic (bone destructive) lesions most com- monly, but also osteoblastic (bone formation), or mixed lytic and blastic bone lesions [2]. Once breast cancer has metastasized to bone, the cancer is incurable and patients suffer from extreme bone pain, skeletal fractures, hypercal- cemia, and nerve compression [2]. Median survival for patients with bone metastases from time of diagnosis is about 2 years [2]. Current treatment with bisphosphonate antiresorptive drugs is palliative and does not improve overall survival [2]. Understanding the bone microenviron- ment, and why breast cancer cells preferentially spread to bone, should reveal new targets for the improved treatment of breast cancer bone metastasis. 2 Breast cancer preferentially spreads to bone Over a hundred years ago, Stephen Paget first noted the nonrandom spread of different types of cancer to distinct organs within the body unexplained by mere blood flow [5]. In an autopsy study of 735 women who died of breast cancer, Paget found that the two most common sites of metastasis were the ovaries and bone [3, 6]. Paget proposed an explanation for why cancer cells only form metastases in particular areas of the body: the seed and soil hypothesis, which states: “when a plant goes to seed, its seeds are carried in all directions; but they can only grow if they fall on congenial soil [6].” The ‘seed’ is the cancer cell, which after circulating through the blood stream, can only ‘grow’ Cancer Metastasis Rev (2006) 25:621–633 DOI 10.1007/s10555-006-9023-1 V. Siclari : T. Guise : J. Chirgwin (*) University of Virginia, Charlottesville, VA, USA e-mail: Jc3qb@virginia.edu V. Siclari e-mail: Vas4a@virginia.edu T. Guise e-mail: Tag4n@virginia.edu