**7. References**


and contributes to the aggressiveness of the disease (Sharp, Sung et al. 1999; Chakraborty, Jain et al. 2008; Hedley, Welch et al. 2008; Patani, Jouhra et al. 2008; Ribeiro-Silva and Oliveira da Costa 2008). In our co-culture model we found, at least in the breast/bone microenvironment, that it was Osteopontin produced by the bone cells, not the breast cells

It is becoming evident that gene expression at the site of breast cancer metastasis may not be the same as at the site of the primary tumour and we need better ways to treat metastases. It will likely be important to biopsy more metastatic tissue to provide the type of designer therapeutics aimed at pathways known to be targetable at the site of the metastasis as we currently do with the primary tumour. Currently, biopsies of metastases are rare. As stroma is known to be an active contributor to the metastasis we also need to develop therapeutic approaches aimed at targeting the stroma. The recent development of new technologies for capture and analysis of circulating tumour cells may help to improve our understanding.

Breast cancer is a complicated disease and progression to metastasis may occur by clonal expansion or parallel progression. Changes in gene expression may occur between the primary tumour and the site of metastasis and development of therapeutics aimed at either the breast or stromal cells at the site of the metastasis will likely be needed to develop better therapeutics against breast cancer metastasis. Some of these new therapeutics may be aimed at reconstituting the expression of breast cancer metastasis inhibitor genes and much research is being done in this field. *In vivo* and *in vitro* model systems have contributed in many ways to our understanding of breast cancer metastasis and will surely continue to do

The authors would like to acknowledge the Alberta Cancer Board and the Canadian Breast Cancer Foundation for research funding. We also thank Brant Pohorelic for careful reading

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**25** 

 *Canada* 

**Breast Cancer Metastases to Bone:** 

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

**1. Introduction** 

metastatic cascade.

**2. Chapter outline** 

 Physiological regulation of breast and bone Breast Growth and Development



**Role of the Microenvironment** 

Jenna E. Fong and Svetlana V. Komarova *Faculty of Dentistry, McGill University, Montreal* 

