**2. Chapter outline**

	- Breast Growth and Development
		- Interactions of normal breast tissue with bone
		- Breast carcinoma
	- Bone Microenvironment

Breast Cancer Metastases to Bone: Role of the Microenvironment 533

content per month (9). Lactation-induced fragility fractures have been reported as a result, but are not common (10). Of interest, other important molecular mediators for the developing of lactating mammary gland are receptor activator of nuclear factorB (RANK) and its ligand RANKL, which are better known for their key role in regulating the formation of osteoclasts. Expression of RANKL in the mammary epithelium is induced by hormones increased during pregnancy, such as prolactin, progesterone, and PTHrP, and mice lacking RANKL or RANK cannot form lobuloalveolar mammary gland structures, resulting in complete inability to develop a lactating mammary gland (11). Thus, normal breast tissue can interact with bone through a system of hormonal regulators that are important during lactation, and it expresses molecular machinery that employs the same mediators to perform locally distinct functions

Fig. 1. Physiological interactions between the functions of breast and bone. Lactation involves secretion of large amounts of calcium. Bone is a key participant in calcium

homeostasis. PTH is reduced during lactation while PTHrP production by the breast tissue is increased. Suckling stimulates prolactin secretion and inhibits GnRH production, both of which reduce estradiol levels, leading to bone resorption. Prolactin and PTHrP induce breast expression of RANKL, necessary for normal lactating mammary gland function. In the bone tissue, osteoblast-produced RANKL is key regulator of osteoclastogenesis.

Breast carcinomas may arise from the inner lining of the milk ducts or from the lobules, known, respectively, as ductal carcinomas or lobular carcinomas (12). Once a tumour exceeds 1-2 mm in diameter, it requires extensive vascularization in order to survive (13), but the speed of cancer growth often exceeds its capability to form normal vascular organization. Poor angiogenesis results in an under-vascularized microenvironment, which leads to hypoxia, acidic pH and nutrient depletion in the tumour (14). Some cancer cells may

(Figure 1).

*Breast carcinoma* 

	- Creation of pre-metastatic niche
	- Migration of breast cancer cells to bone
	- Attachment proteins between breast cancer cells and the bone
	- Osteomimicry
	- Interactions with osteoblasts
		- Inhibition of osteoblasts by breast cancer cells
		- Contribution of osteoblasts to the creation of an osteolytic environment
		- Role of osteoblasts in supporting breast cancer cells
	- Interactions with osteoclasts
		- Stimulation of osteoclasts by breast cancer cells
		- Role of osteoclasts in supporting breast cancer cells
