Rb deletion in mouse mammary progenitors induces luminal-B or basal-like/EMT tumor subtypes depending on p53 status

• Published in: The Journal of clinical investigation Vol. 120; no. 9; pp. 3296 - 3309
• Main Authors: Jiang, Zhe, Deng, Tao, Jones, Robert, Li, Huiqin, Herschkowitz, Jason I., Liu, Jeff C., Weigman, Victor J., Tsao, Ming-Sound, Lane, Timothy F., Perou, Charles M., Zacksenhaus, Eldad
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.09.2010
• Subjects: Animals; Apoptosis; Biomedical research; Breast cancer; Breastfeeding & lactation; Cancer; Cell cycle; Cell Line; Epidermal growth factor; Estrogens; Female; Females; Gene Deletion; Gene expression; Genes, p53; Genes, Retinoblastoma; Genetic aspects; Histology; Humans; Mammary Glands, Animal - metabolism; Mammary Glands, Animal - pathology; Mammary Neoplasms, Experimental - genetics; Mammary Neoplasms, Experimental - pathology; Mice; Mice, Knockout; Mutation; Physiological aspects; Progesterone; Properties; Proteins; Retinoblastoma; Stem Cells - metabolism; Tumor proteins; Tumor Suppressor Protein p53 - genetics; Tumors; United States
• ISSN: 0021-9738; 1558-8238; 1558-8238
• DOI: 10.1172/JCI41490

Breast cancer is a highly heterogeneous disease, with several different subtypes being characterized by distinct histology, gene expression patterns, and genetic alterations. The tumor suppressor gene retinoblastoma 1 (RB1) is frequently lost in both luminal-B and triple-negative tumor (TNT; i.e., estrogen receptor-, progesterone receptor-, and human epidermal growth factor receptor 2-negative) breast cancer subtypes. However, a causal role for RB1 loss in different subtypes remains undefined. Here we report that deletion of Rb alone or together with its relative p107 in mouse mammary stem/bipotent progenitor cells induced focal acinar hyperplasia with squamous metaplasia. These lesions progressed into histologically diverse, transplantable mammary tumors with features of either luminal-B or TNT subtypes. The TNTs included basal-like tumors as well as tumors that exhibited epithelial-to-mesenchymal transition (EMT). The EMT-type tumors and a subset of the basal-like tumors, but not luminal-B-like tumors, expressed mutant forms of the tumor suppressor p53. Accordingly, targeted deletion of both Rb and p53 in stem/bipotent progenitors led to histologically uniform, aggressive, EMT-type tumors. Reintroduction of Rb into these tumor cells suppressed growth in vitro and tumor formation in vivo. These results establish a causal role for Rb loss in breast cancer in mice and demonstrate that cooperating oncogenic events, such as mutations in p53, dictate tumor subtype after Rb inactivation.