title: DMBA induced mouse mammary tumors display high incidence of activating Pik3caH1047 and loss of function Pten mutations.
abstract: Controversy always existed on the utility of chemically induced mouse mammary carcinogenesis models as valid equivalents for the study of human breast cancer. Here, we performed whole exome and RNA sequencing on long latency mammary tumors (218 ± 27 days) induced by the carcinogen 7,12-Dimethylbenzathracene (DMBA) and short latency tumors (65 ± 11 days) induced by the progestin Medroxyprogesterone Acetate (MPA) plus DMBA in CD2F1 mice. Long latency tumors displayed a high frequency of Pi3kca and/or Pten mutations detected in 11 of 13 (85%) long latency cases (14/22, 64% overall). Eighty-two percent (9/11) of tumors carried the Pik3ca H1047L/R hot-spot mutation, as frequently found in human breast cancer. These tumors were luminal-like and mostly ER/PR+, as in humans. Transcriptome profiling indicated a significant activation of the PI3K-Akt pathway (p=3.82e-6). On the other hand MPA+DMBA induced short latency tumors displayed mutations in cancer drivers not commonly found mutated in human breast cancer (e.g. Hras and Apc). These tumors were mostly basal-like and MPA exposure led to Rankl overexpression (60 fold induction) and immunosuppressive gene expression signatures. In summary, long latency DMBA induced mouse mammary tumors reproduce the molecular profile of human luminal breast carcinomas representing an excellent preclinical model for the testing of PIK3CA/Akt/mTOR pathway inhibitory therapies and a good platform for the developing of additional preclinical tools such as syngeneic transplants in immunocompetent hosts.
authors: CINIBA, Facultad de Ciencias Médicas, Universidad Nacional de La Plata, Argentina.|CAETI, Facultad de Tecnología Informática, Universidad Abierta Interamericana (UAI), Argentina.
authors: Martín C
authors: MC
authors: Abba
authors: Department of Epigenetics and Molecular Carcinogenesis, University of Texas, M.D. Anderson Cancer Center, Smithville, TX, USA.
authors: Yi
authors: Y
authors: Zhong
authors: Department of Epigenetics and Molecular Carcinogenesis, University of Texas, M.D. Anderson Cancer Center, Smithville, TX, USA.
authors: Jaeho
authors: J
authors: Lee
authors: Department of Epigenetics and Molecular Carcinogenesis, University of Texas, M.D. Anderson Cancer Center, Smithville, TX, USA.
authors: Hyunsuk
authors: H
authors: Kil
authors: Department of Epigenetics and Molecular Carcinogenesis, University of Texas, M.D. Anderson Cancer Center, Smithville, TX, USA.
authors: Yue
authors: Y
authors: Lu
authors: Department of Epigenetics and Molecular Carcinogenesis, University of Texas, M.D. Anderson Cancer Center, Smithville, TX, USA.
authors: Yoko
authors: Y
authors: Takata
authors: Department of Epigenetics and Molecular Carcinogenesis, University of Texas, M.D. Anderson Cancer Center, Smithville, TX, USA.
authors: Melissa S
authors: MS
authors: Simper
authors: Department of Epigenetics and Molecular Carcinogenesis, University of Texas, M.D. Anderson Cancer Center, Smithville, TX, USA.
authors: Sally
authors: S
authors: Gaddis
authors: Department of Epigenetics and Molecular Carcinogenesis, University of Texas, M.D. Anderson Cancer Center, Smithville, TX, USA.
authors: Jianjun
authors: J
authors: Shen
authors: Department of Epigenetics and Molecular Carcinogenesis, University of Texas, M.D. Anderson Cancer Center, Smithville, TX, USA.
authors: C Marcelo
authors: CM
authors: Aldaz
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D058534:Class I Phosphatidylinositol 3-Kinases; D004252:DNA Mutational Analysis; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D017258:Medroxyprogesterone Acetate; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism; D017423:Sequence Analysis, RNA; D013997:Time Factors; D059467:Transcriptome; D000073359:Exome Sequencing
chemical_list: D015127:9,10-Dimethyl-1,2-benzanthracene; D058534:Class I Phosphatidylinositol 3-Kinases; D017258:Medroxyprogesterone Acetate; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D053245:RANK Ligand; C505689:Tnfsf11 protein, mouse; C546639:Pik3ca protein, mouse; C487757:Pten protein, mouse
keywords: DMBA; MPA; Pik3ca; Pten; mammary tumors