Serial transplantation of NMU-induced rat mammary tumors: A model of human breast cancer progression

Human breast cancer is a heterogeneous disease that appears to progress from an in situ tumor to invasive cancer. Little is known about the molecular events driving this progression. Although microarray technology has helped us understand the genetic heterogeneity of breast cancer, its application to studying the transition from in situ to invasive disease is limited by the inability to follow the progression of a single patient's tumor. We previously used rat specific microarrays to show that N-methyl-N-nitrosourea induced tumors are similar to low-grade estrogen- receptor positive human breast cancer. Here, we transplanted these tumors through 5 generations of syngeneic hosts, and studied 65 resulting tumors. Most transplanted tumors gradually progressed from a noninvasive, low-grade cancer to a higher-grade invasive disease, losing p63 localization and basement membrane integrity. Invasive cancers frequently demonstrated a more mesenchymal phenotype with increased vimentin expression. Additionally, a unique transplant series is described with a phenotype similar to human basal-like breast cancer. Rat-specific Affymetrix gene arrays containing 15,866 gene probes identified genes that differentiated highly invasive tumors from those of low invasive potential. A linear regression analysis was used to find genes whose change in expression paralleled increasing invasive features independent of the transplant lineage of origin. Genes identified were assigned membership in cell adhesion, signal transduction, cell cycle and extracellular matrix groups, among others. This animal model overcomes the difficulty in studying human breast cancer progression. Our data support a gradual and continuous alteration in programs of gene expression during breast cancer invasion. (c) 2007 Wiley-Liss, Inc.