Rb deletion in mouse mammary progenitors induces luminal-B or basal-like/EMT tumor subtypes depending on p53 status.
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.
Jiang
Zhe
Z
Division of Cell and Molecular Biology, Toronto General Research Institute-University Health Network, Toronto, Ontario, Canada.
Deng
Tao
T
Jones
Robert
R
Li
Huiqin
H
Herschkowitz
Jason I
JI
Liu
Jeff C
JC
Weigman
Victor J
VJ
Tsao
Ming-Sound
MS
Lane
Timothy F
TF
Perou
Charles M
CM
Zacksenhaus
Eldad
E
D000818:Animals; D002460:Cell Line; D005260:Female; D017353:Gene Deletion; D016161:Genes, Retinoblastoma; D016158:Genes, p53; D006801:Humans; D008321:Mammary Glands, Animal / Q000378:metabolism / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000235:genetics* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D013234:Stem Cells / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
D016159:Tumor Suppressor Protein p53