Breast cancer models: Engineering the tumor microenvironment.

The mechanisms behind cancer initiation and progression are not clear. Therefore, development of clinically relevant models to study cancer biology and drug response in tumors is essential. In vivo models are very valuable tools for studying cancer biology and for testing drugs; however, they often suffer from not accurately representing the clinical scenario because they lack either human cells or a functional immune system. On the other hand, two-dimensional (2D) in vitro models lack the three-dimensional (3D) network of cells and extracellular matrix (ECM) and thus do not represent the tumor microenvironment (TME). As an alternative approach, 3D models have started to gain more attention, as such models offer a platform with the ability to study cell-cell and cell-material interactions parametrically, and possibly include all the components present in the TME. Here, we first give an overview of the breast cancer TME, and then discuss the current state of the pre-clinical breast cancer models, with a focus on the engineered 3D tissue models. We also highlight two engineering approaches that we think are promising in constructing models representative of human tumors: 3D printing and microfluidics. In addition to giving basic information about the TME in the breast tissue, this review article presents the state-of-the-art tissue engineered breast cancer models. STATEMENT OF SIGNIFICANCE: Involvement of biomaterials and tissue engineering fields in cancer research enables realistic mimicry of the cell-cell and cell-extracellular matrix (ECM) interactions in the tumor microenvironment (TME), and thus creation of better models that reflect the tumor response against drugs. Engineering the 3D in vitro models also requires a good understanding of the TME. Here, an overview of the breast cancer TME is given, and the current state of the pre-clinical breast cancer models, with a focus on the engineered 3D tissue models is discussed. This review article is useful not only for biomaterials scientists aiming to engineer 3D in vitro TME models, but also for cancer researchers willing to use these models for studying cancer biology and drug testing.