**1.2.1 Cells of the breast microenvironment**

The abnormal epithelial cells composing a breast carcinoma form only one component of a complex microenvironment which influences the success or failure of a developing tumour. In fact the breast tumour microenvironment consists also of multiple cell types; including myoepithelial cells, fibroblasts, endothelial cells and immune cells such as macrophages (Figure 2). In terms of their likely contributions to breast tumourigenesis, fibroblasts and macrophages are often considered as tumour promoters through downstream signalling from various secreted factors, while the endothelial cells which develop in tumourassociated blood vessels also support cancer development. In contrast, myoepithelial cells exert functions broadly considered as tumour-suppressive.

Fibroblasts are an important structural component of the extracellular environment in the normal breast, where they help control the development of the breast epithelium (McCave *et al*. 2010). Their secretion of extracellular matrix components and cytokines has also implicated them in tumorigenic growth associated with invasive breast cancer (Orimo *et al*., 2005), and differences in cellular responsiveness to normal versus tumour-derived fibroblasts have been noted (Sadlonova *et al*., 2005). Many studies have highlighted the

Fig. 2. Diagram of a normal breast duct depicting cells of the microenvironment.

The abnormal epithelial cells composing a breast carcinoma form only one component of a complex microenvironment which influences the success or failure of a developing tumour. In fact the breast tumour microenvironment consists also of multiple cell types; including myoepithelial cells, fibroblasts, endothelial cells and immune cells such as macrophages (Figure 2). In terms of their likely contributions to breast tumourigenesis, fibroblasts and macrophages are often considered as tumour promoters through downstream signalling from various secreted factors, while the endothelial cells which develop in tumourassociated blood vessels also support cancer development. In contrast, myoepithelial cells

Fibroblasts are an important structural component of the extracellular environment in the normal breast, where they help control the development of the breast epithelium (McCave *et al*. 2010). Their secretion of extracellular matrix components and cytokines has also implicated them in tumorigenic growth associated with invasive breast cancer (Orimo *et al*., 2005), and differences in cellular responsiveness to normal versus tumour-derived fibroblasts have been noted (Sadlonova *et al*., 2005). Many studies have highlighted the

**1.2.1 Cells of the breast microenvironment** 

exert functions broadly considered as tumour-suppressive.

potential involvement of fibroblasts in promoting tumour progression both at genomic and transcriptomic levels, with reports of altered genetic signatures between normal and tumour-associated fibroblasts supporting a complex role for fibroblasts in influencing tumour progression (Hu *et al.,* 2005; Hu *et al.,* 2008; Ma *et al*., 2009).

Macrophages within the breast cancer microenvironment have been shown to enhance tumour growth through the secretion of pro-angiogenic factors like vascular endothelial growth factor (VEGF); (Murdoch *et al*., 2004; Lamagna *et al*., 2005 ; Lewis & Hughes, 2007). They have also been implicated in promoting a metastatic phenotype, via the secretion of pro-migratory factors such as EGF (Wyckoff *et al*., 2004) which enhance cellular dissemination from a primary tumour. Accordingly, the enhanced physical juxtaposition of macrophages, tumour cells and endothelial cells has been proposed as a new prognostic histopathological marker associated with increased risk of metastases in human breast cancer (Robinson *et al*., 2009).

Endothelial cells which line the blood vessels are derived from angioblasts forming the vascular network. Enhanced vessel density occurring as a result of tumour-associated angiogenesis is a major contributor to both the survival of primary breast tumours (via the delivery of systemic growth factors) and the risk of metastasis (via increased access of disseminated tumour cells to a circulatory source). Expression of pro-angiogenic factors such as VEGF has been shown to increase in haematological malignancies (Fiedler *et al*., 1997; Molica *et al*., 1999) in addition to solid tumours including breast, renal, ovarian, gastric and lung cancer (Patel *et al*., 2009; Burger, 2011; Gou *et al*., 2011; Sharma *et al*., 2011). VEGF promotes neovascularisation via mitogenic and pro-migratory effects on endothelial cells (Asahara *et al*., 1999).

Finally, myoepithelial cells are known to play a role in the formation of the basement membrane and thereby assist in maintaining polarity of the breast ductal epithelium. They also interact with epithelial cells to regulate the cell cycle and suppress breast cancer cell growth, invasion and angiogenesis (Weaver *et al*., 1996; Alpaugh *et al*., 2000; Barsky, 2003). Tumour and non-tumour primary myoepithelial cells have been described to differ in functional properties relating to the secretion of extracellular matrix components such as laminin-1 (Gudjonsson *et al*., 2002), and accordingly myoepithelial cells reportedly lose their established tumour-suppressive properties during tumour progression (Polyak & Hu, 2005). Taken together, the many cell types within the breast tumour microenvironment can both individually and coordinately regulate several functions relevant to tumour progression. In order to better understand their relative contributions to breast cancer, it is necessary to dissect the signals that regulate their own functions. Since adhesive functions are central to the behaviour of all of these cell types, the remainder of this chapter will focus on their potential regulation by a family of adhesion proteins termed the Junction Adhesion Molecules (JAMs), whose role in breast cancer initiation and progression is just emerging.
