Modeling dynamic reciprocity: engineering three-dimensional culture models of breast architecture, function, and neoplastic transformation

Abstract

In order to understand why cancer develops as well as predict the outcome of pharmacological treatments, we need to model the structure and function of organs in culture so that our experimental manipulations occur under physiological contexts. This review traces the history of the development of a prototypic example, the three-dimensional (3D) model of the mammary gland acinus. We briefly describe the considerable information available on both normal mammary gland function and breast cancer generated by the current model and present future challenges that will require an increase in its complexity. We propose the need for engineered tissues that faithfully recapitulate their native structures to allow a greater understanding of tissue function, dysfunction, and potential therapeutic intervention.

Fig. 1

Structure and 3D model of mammary gland. (A) Luminal epithelial cells (LEP) forming the acinus are regulated by homotypic interactions with neighboring luminal cells, by heterotypic interactions with myoepithelial cells (MEP), and by interactions with the BM. The bi-layered structure is surrounded by a complex BM and a stroma comprised of stromal ECM, fibroblasts, and adipocytes, as well as nerves, blood, and lymphatic vessels (not depicted). This structure is disrupted in tumors. Additionally, myoepithelial cells surrounding the tumor have altered function [105,130]. (B) (left) In the 3D model of the normal mammary gland acinus, human or mouse mammary epithelial cells cultured in or on laminin-1-rich, malleable BM will form spherical structures with a central lumen. Addition of lactogenic hormones to mouse cells leads to the synthesis and vectorial secretion of milk proteins into the lumen (milk production by non-malignant human epithelial cells has not yet been achieved). Luminal epithelial cells fail to organize into an acinus when cultured in 3D collagen gels unless they receive signals from myoepithelial cells, which synthesize the laminin components of BM. (right) Oncogenic insults prevent tumorigenic epithelial cells from forming the acinus; these tumorigenic structures can be functionally reverted by restoring normal signaling pathways [52]. (B) modified from [131]. Red, BM; blue, MEPs; white/grey, LEPs; green, sialomucin.

Fig. 2

The tissue-engineered breast. New strategies should enable the control of the microenvironment at the nano-, micro-, and macro-scales with temporal precision. (A) Synthetic and recombinant ECM polymers impart cues sensed directly by cell-surface receptors. (B–C) Microfabricated constructs control the positions of multiple cell types with respect to each other and the ECM with micrometer precision across large areas of tissue. (D) Engineered breast tissues that can be visualized and manipulated in real time.