Reprogramming breast cancer cells with embryonic microenvironments: Insights from Nodal signaling

Normal developmental pathways that determine cell fate, migration, and proliferative potential become reactivated in cancer to promote the most devastating aspect of the disease, namely, metastasis to new sites. However, unlike their function in the delimited process of normal growth and differentiation, developmental pathways in the context of metastatic cancer support an aberrant and unlimited morphogenic program. Understanding how specific morphogenic pathways function in normal development and how they become deregulated in cancer may provide insight into new therapeutic opportunities to limit cancer spread. Adding complexity, however, such developmental pathways do not function solely through linear, cell autonomous programs but rather as dynamic, iterative processes between cells and their microenvironment. Therefore, comprehensive strategies to treat cancer and limit recurrence and metastasis must consider the ever-changing, reciprocal developmental relationship of cancer cells with their microenvironment. One important developmental pathway that shapes the interdependent evolution of breast cancer cells and their microenvironment is signaling by the embryonic morphogen Nodal, a member of the TGF-β family and a promising, new therapeutic target. Herein we review the significance of bidirectional signaling with the microenvironment in tumor progression and the distorted recapitulation of normal developmental programs that promote tumor aggression. Further, this chapter examines the reemergence of Nodal signaling during breast cancer growth and, finally, the therapeutic potential of targeting cancer cell-microenvironment interactions in general, and particularly Nodal signaling, to reprogram these relationships and promote a more benign developmental course in malignant breast cancer.