Functional Disruption of the Netrin-1 Guidance Gue Leads to Disruption in Mammary Gland Development and Increased Tumor Incidence

摘要

My laboratory discovered a mammary receptor for the "axon guidance" cue netrin-1 (Ntn1) called neogenin, and I proposed to examine the stromal phenotype associated with the loss of function of neogenin using transplant analysis. Analysis of homozygous null mammary tissue versus wildtype revealed no changes in tissue morphology due to the loss of neogenin function during any stage of mammary gland development. During these studies, we observed a synergistic relationship between netrin-1 and another "axon guidance" cue, Slit2. Importantly, many studies have linked misexpression of Slit proteins with breast cancer progression. while Slit2 null mammary glands displayed a phenotype similar to Ntn1 null glands, glands harboring homozygous null mutations in both Ntn1 and Slit2 showed an enhanced phenotype that extended through the ducts and was characterized by separated cell layers, occluded lumens and hyperplasia. Our data demonstrate that these new proteins, originally identified in the nervous system, play critical roles during gland development and disease.