Pathobiology 75:335–345CrossRefPubMed”
“Introduction Breast tumorigenesis is a multifaceted process involving molecular and functional alterations in both the stromal and epithelial compartments of the breast. The interaction between these two compartments is important in the tumorigenic process and is rooted in a complex network of molecules belonging to families of growth factors, immunomodulatory factors, steroid hormones, and extracellular matrix (ECM) components and proteases [1–3]. 4SC-202 molecular weight Several studies indicate that stromal fibroblasts

surrounding normal and cancerous breast epithelium exert a modulatory effect on the epithelium, the nature of which is dependent upon the state of the fibroblasts

and the epithelium [3–5]. Specifically, APR-246 ic50 stromal fibroblasts in normal breast serve a protective function and exert inhibitory signals on the growth of normal epithelium, while cancer-associated stromal fibroblasts act more permissively and allow or promote growth of normal and cancer epithelium. In vitro studies with normal-breast associated fibroblasts (NAF) demonstrate that NAF inhibit the growth of the non-tumorigenic breast epithelial cell line, MCF10A, and its more transformed, tumorigenic derivative, MCF10AT [3, 5]. In vivo, admixed NAF exert an inhibitory effect on histologically normal epithelium but also limit cancer development and growth as shown in the MCF10AT xenograft model of proliferative breast disease [6]. Conversely, fibroblasts derived from breast cancer tissues (CAF) possess permissive or promoting abilities for epithelial cell growth both in vitro and in vivo and exhibit molecular and functional characteristics similar to that of activated stromal

fibroblasts normally associated with wound healing [3, 4]. In contrast to NAF, CAF proliferate at a higher rate and secrete increased levels of growth factors, ECM proteins and immunomodulatory factors [2, 7–9]. The ability of CAF to modulate epithelial cell growth is dependent on the phenotype of the corresponding epithelium. ID-8 As has been previously shown, CAF inhibit the growth of the MCF10A cells in vitro [3] but promote the growth of breast cancer cell lines, such as MCF-7, in vitro and in vivo [4, 10, 11]. Therefore, the biologic effect of CAF is influenced by the molecular and functional properties of the CAF and the responsiveness of the epithelial cells. Only a few specific molecules derived from CAF, such as Stromal Derived Factor 1 and Hepatocyte Growth Factor, have been shown to contribute to the tumorigenic process [4, 12]. Given the complexity of these stromal–epithelial GSK2126458 cell line interactions and the molecular heterogeneity of breast cancers, there are likely many more fibroblast-derived molecules important in breast carcinogenesis and cancer progression that remain to be identified.