Molecular analysis reveals heterogeneity of mouse mammary tumors conditionally mutant for BrcaI

Background: Development of therapies for patients with BRCAI mutations has been hampered by lack of readily available in vitro and in vivo models. We recently showed that transplantation of transgenic mammary tumors as cell suspensions into naive recipients generates reproducible tumors with remarkable stability of gene expression profile. We examined the expression profiles of original and serially transplanted mammary tumors from BrcaI deficient mice, and tumor derived cell lines to validate their use for preclinical testing and studies of tumor biology. Methods: Original tumors, serially transplanted and multiple cell lines derived from BrcaI mammary tumors were characterized by morphology, gene and protein expression, and cell surface markers. Results: Gene expression among BrcaI tumors showed more heterogeneity than among previously characterized tumors from MMTV-PyMT and -WntI models. Gene expression data segregated BrcaI tumors into 3 distinct types: basal, mixed luminal, and tumors with epithelial-to-mesenchymal transition (EMT). Serial transplantation of individual tumors and multiple cell lines derived from the original tumors recapitulated the molecular characteristics of each tumor of origin. One tumor had distinct features of EMT and gave rise to cell lines that contained a distinct CD44(+)/CD24-/low population that may correlate with human breast cancer stem cells. Conclusion: Although individual tumors expanded by transplantation maintain the genomic profile of the original tumors, the heterogeneity among BrcaI tumors limits the extent of their use for preclinical testing. However, cell lines offer a robust material for understanding tumor biology and response to therapies driven by BRCAI deficiency.

See More