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1. Introduction
It is now becoming increasingly clear that cancer is not a single disease and that it is
organ- and tissue-specific. Further, even within a single organ, such as the mammary
gland, tumors are heterogeneous with respect to histology, gene expression and
clinical outcome. In order to advance our understanding of the complex biology of
breast cancer and eventually to improve clinical management of the disease, we need
experimental model systems that recapitulate the in vivo functions, interactions and
architecture of the mammary gland and breast tumors.
The mammary gland, like many glandular organs, is embedded in stroma, which is
composed of mesenchymal cells, such as fibroblasts, adipocytes, immune cells and
extracellular matrix (ECM). Our laboratory postulated long ago that the ECM not only
provides structural support but also signaling cues via transmembrane receptors,
directing cytoskeletal and chromatin organization to maintain tissue integrity [1,2].
More than two decades ago, it was shown that collagen gels, which provide a 3D
scaffold, allow epithelial cells of various tissues and origins to maintain some of their
tissue structure and differentiated functions [3-6]. Building on these first observations,
we developed 3D culture systems using either collagen gels [7,8] or, more importantly
for epithelial cells, laminin-rich extracellular matrices (lrECM) to study tissue-
specific functions of normal mouse mammary cells [9,10] as well as normal and
malignant human cells [11]. In parallel with our experiments, others developed
cultures for rat hepatocytes [12]. Since then, the in vivo-like properties provided by
the 3D model systems has received broader appreciation and has been adopted for the
study of diverse tissues and cells besides mammary luminal epithelial cells and
hepatocytes such as skin [13,14], muscle [15], colon [16], bile duct [17], esophagus
[18], as well as adipocytes [19], fibroblasts [20,21] and embryonic stem cells [22,23]
among others.
In this review, we first depict how 3D cell culture models can be utilized to dissect
signaling pathways that regulate function of normal and malignant mammary
epithelial structures. We further describe the potential of these models for applied
breast cancer research, namely the identification of prognostic and predictive profiles
and therapeutic screening. Second, we discuss the future challenges we will have to
face in order to bring the understanding of breast cancer and its treatment to full
fruition.
