The retinoblastoma (Rb) and p53 tumor suppressor pathways are frequently altered in human malignancies including breast cancer. To investigate the role of these pathways in mammary tumorigenesis, we crossed mice expressing Cre recombinase in the mammary epithelium (MMTV-Cre) with mice harboring Rb and p53 floxed alleles to generate MMTV-Cre:Rbf/f:p53f/f mutant mice. Combined somatic loss of Rb and p53 led to the formation of aggressive triple-negative tumors (ER−, PR−, HER2−) that often displayed features of an epithelial to mesenchymal transition (EMT) including sarcomatoid differentiation and high expression of the mesenchymal marker N-Cadherin. Molecular profiling revealed Rb/p53 deficient tumors shared similar gene expression profiles with mouse and human claudin-low breast cancers. Interstingly, limiting dilution transplantation analysis also suggests that Rb/p53 deficient claudin-low tumors are enriched for tumor-initiating cells (TICs).

To investigate the cellular origin of claudin-low tumors, the Rbf/f and p53f/f alleles were deleted within the luminal and basal compartments of the mammary gland using a Cre-expressing adenovirus (Ad-Cre) and CD24-CD49f-based FACS analysis. The different cellular fractions were then transplanted into the cleared mammary fat pad of recipient mice which are currently being monitored for tumor development.

Finally, primary cell lines isolated from Rb/p53 deficient mammary tumors were used in conjunction with high-throughput chemical and genetic screens to identify new therapeutic targets. A primary screen of 260 kinase inhibitors and 312 FDA-approved off-patent drugs has identified novel candidates and a genome wide negative selection (‘drop-out’) screen is currently in progress.

Ultimately, the results of this research will provide important insight into the biology of triple-negative breast cancer and will lead to the identification of novel therapeutic targets for the treatment of patients living with this disease.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-04-05.

This abstract was not presented at the conference.

2012