**2. The breast tumor microenvironment**

A normal epithelial tissue can undergo hyperplasia and acquire tumorigenic properties that promote the development of a benign, non-invasive solid tumor known as carcinoma *in situ*. Normal epithelial tissues and non-invasive carcinoma *in situ* tumors are separated from a supportive stromal compartment by an intact basement membrane. Ultimately, carcinoma *in situ* can progress to a malignant, invasive carcinoma, the most common form of human cancer. The panoply of published investigations between the fields of mammary gland development and breast cancer has led to an appreciation for a supportive non-epithelial mammary stroma that mechanically and biologically restrains tumorigenesis. However, tumors of the breast and other epithelial tissues obviously overcome these growth restraints and exploit this stroma to sculpt a vastly divergent tumor stroma. Tumor stroma is generally divided into four main components: tumor vasculature, inflammatory leukocytes, extracellular matrix (ECM) and soluble growth factors, and fibroblasts. Malignant carcinoma cells and tumor stromal cells bi-directionally communicate with one another through paracrine signaling and intercellular contacts in a disorganized ECM to constitute a tumor microenvironment. Tumor-associated fibroblasts (TAF), the predominant stromal cell population within the tumor microenvironment, acquire and sustain an "activated" phenotype that promotes tumor progression (Rasanen and Vaheri, 2010). TAF are capable of enhancing breast tumor growth and metastasis by means of promoting angiogenesis (Orimo *et al.*, 2005), epithelial-mesenchymal transition (EMT) (Martin *et al.*, 2010; Radisky *et al.*, 2005), and progressive genetic instability (Kurose *et al.*, 2001; Moinfar *et al.*, 2000). In contrast, a normal mammary microenvironment can act in a dominant manner to inhibit tumor growth and "revert" the malignant phenotype of breast cancer cells (Kenny and Bissell, 2003). While resident breast tissue fibroblasts can inhabit breast tumors as TAF, breast tumors also recruit distant cell populations that engraft within the breast tumor microenvironment where they actively contribute as TAF. For example, mesenchymal stem cells (MSC), a bone marrow-derived stromal cell population, home to breast cancer cell xenograft tumors and persist as TAF (Spaeth *et al.*, 2009).
