Tumor microenvironment plays a critical role in regulating
tumor progression by secreting factors that mediate
cancer cell growth. Stromal fibroblasts can promote
tumor growth through paracrine factors; however, restraint of malignant
carcinoma progression by the microenvironment also has been observed. The mechanisms that underlie this paradox remain unknown. Here, we report that the tumorigenic potential of
breast cancer cells is determined by an interaction between the Robo1 receptor and its
ligand Slit2, which is secreted by stromal fibroblasts. The presence of an active Slit2/Robo1 signal blocks the translocation of β-
catenin into nucleus, leading to downregulation of c-myc and
cyclin D1 via the
phosphoinositide 3-kinase (PI3K)/Akt pathway. Clinically, high Robo1 expression in the
breast cancer cells correlates with increased survival in patients with
breast cancer, and low Slit2 expression in the stromal fibroblasts is associated with
lymph node metastasis. Together, our findings explain how a specific tumor microenvironment can restrain a given type of
cancer cell from progression and show that both stromal fibroblasts and
tumor cell heterogeneity affect
breast cancer outcomes.