**1. Introduction**

530 Breast Cancer – Focusing Tumor Microenvironment, Stem Cells and Metastasis

Wagner, W. and A. D. Ho (2007). "Mesenchymal stem cell preparations--comparing apples

Wagner, W., C. Roderburg, et al. (2007). "Molecular and secretory profiles of human

Weaver, V. M., A. H. Fischer, et al. (1996). "The importance of the microenvironment in

Welch, D. R. (1997). "Technical considerations for studying cancer metastasis in vivo." Clin

Yang, X., L. L. Wei, et al. (2001). "Overexpression of KAI1 suppresses in vitro invasiveness and in vivo metastasis in breast cancer cells." Cancer Res 61(13): 5284-5288. Yang, X., D. R. Welch, et al. (1997). "KAI1, a putative marker for metastatic potential in

mesenchymal stromal cells and their abilities to maintain primitive hematopoietic

breast cancer progression: recapitulation of mammary tumorigenesis using a unique human mammary epithelial cell model and a three-dimensional culture

and oranges." Stem Cell Rev 3(4): 239-248.

progenitors." Stem Cells 25(10): 2638-2647.

assay." Biochem Cell Biol 74(6): 833-851.

human breast cancer." Cancer Lett 119(2): 149-155.

Exp Metastasis 15(3): 272-306.

Bone is the preferred site for breast cancer metastasis, which leads to altered mineral metabolism, disruption of bone architecture, and considerable pain burden. Prior to homing to the bone, the primary breast tumour releases soluble factors that lead to the creation of a pre-metastatic niche in the bone, which then serves to attract and maintain invading breast cancer cells. Breast cancer cells actively influence resident bone cells, altering both the action of and cross-talk between bone forming osteoblasts and bone-destroying osteoclasts. Breast cancer cells inhibit osteoblast differentiation and prevent them from creating and mineralizing new bone. Immature osteoblasts act as part of a hematopoietic stem cell niche and provide an attachment site for breast cancer cells. Breast cancer cells also produce factors, such as parathyroid hormone-related protein (PTHrP), which induce osteoblasts to stimulate the production of the pro-resorptive cytokine RANKL and to inhibit the production of RANKL inhibitor, OPG. RANKL, together with other osteoclastogenic factors released from breast cancer cells, promotes the fusion and differentiation of osteoclasts, resulting in bone destruction. As a result of bone resorption, growth factors stored in the bone matrix, such as TGF, are released and can further stimulate the proliferation and survival of tumour cells. Thus, the complex interactions between breast cancer cells and the bone microenvironment underlie the homing of the breast cancer to bone and the subsequent progression of osteolytic lesions. Current therapeutics against bone metastases aim to prevent osteoclastic bone resorption by blocking osteoclast differentiation or stimulating their apoptosis. The osteoblast provides a valuable potential target, as a source of osteoclastic differentiation factors, and a platform for cancer cell attachment. Recent results from basic and clinical research provide new targets to prevent the interactions between breast cancer cells and the bone microenvironment at different stages of the metastatic cascade.
