DMBA induced mouse mammary tumors display high incidence of activating Pik3ca<sup>H1047</sup> and loss of function Pten mutations

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-Dimethylbenza...

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Autores principales: Abba, Martín Carlos, Zhong, Yi, Lee, Jaeho, Kil, Hyunsuk, Lu, Yue, Takata, Yoko, Simper, Melissa S., Gaddis, Sally, Shen, Jianjun, Aldaz, C. Marcelo
Formato: Articulo
Lenguaje:Inglés
Publicado: 2016
Materias:
Ciencias Médicas
DMBA
Mammary tumors
MPA
Pik3ca
Pten
Acceso en línea:http://sedici.unlp.edu.ar/handle/10915/86650
Aporte de:
SEDICI (UNLP) de Universidad Nacional de La Plata
id I19-R120-10915-86650
record_format dspace
institution Universidad Nacional de La Plata
institution_str I-19
repository_str R-120
collection SEDICI (UNLP)
language Inglés
topic Ciencias Médicas
DMBA
Mammary tumors
MPA
Pik3ca
Pten
spellingShingle Ciencias Médicas
DMBA
Mammary tumors
MPA
Pik3ca
Pten
Abba, Martín Carlos
Zhong, Yi
Lee, Jaeho
Kil, Hyunsuk
Lu, Yue
Takata, Yoko
Simper, Melissa S.
Gaddis, Sally
Shen, Jianjun
Aldaz, C. Marcelo
DMBA induced mouse mammary tumors display high incidence of activating Pik3ca<sup>H1047</sup> and loss of function Pten mutations
topic_facet Ciencias Médicas
DMBA
Mammary tumors
MPA
Pik3ca
Pten
description 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 <i>Pi3kca</i> and/or <i>Pten</i> mutations detected in 11 of 13 (85%) long latency cases (14/22, 64% overall). Eighty-two percent (9/11) of tumors carried the <i>Pik3ca</i> H1047L/R hotspot mutation, as frequently found in human breast cancer. These tumors were luminallike 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. <i>Hras</i> and <i>Apc</i>). These tumors were mostly basal-like and MPA exposure led to <i>Rankl</i> 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.
format Articulo
Articulo
author Abba, Martín Carlos
Zhong, Yi
Lee, Jaeho
Kil, Hyunsuk
Lu, Yue
Takata, Yoko
Simper, Melissa S.
Gaddis, Sally
Shen, Jianjun
Aldaz, C. Marcelo
author_facet Abba, Martín Carlos
Zhong, Yi
Lee, Jaeho
Kil, Hyunsuk
Lu, Yue
Takata, Yoko
Simper, Melissa S.
Gaddis, Sally
Shen, Jianjun
Aldaz, C. Marcelo
author_sort Abba, Martín Carlos
title DMBA induced mouse mammary tumors display high incidence of activating Pik3ca<sup>H1047</sup> and loss of function Pten mutations
title_short DMBA induced mouse mammary tumors display high incidence of activating Pik3ca<sup>H1047</sup> and loss of function Pten mutations
title_full DMBA induced mouse mammary tumors display high incidence of activating Pik3ca<sup>H1047</sup> and loss of function Pten mutations
title_fullStr DMBA induced mouse mammary tumors display high incidence of activating Pik3ca<sup>H1047</sup> and loss of function Pten mutations
title_full_unstemmed DMBA induced mouse mammary tumors display high incidence of activating Pik3ca<sup>H1047</sup> and loss of function Pten mutations
title_sort dmba induced mouse mammary tumors display high incidence of activating pik3ca<sup>h1047</sup> and loss of function pten mutations
publishDate 2016
url http://sedici.unlp.edu.ar/handle/10915/86650
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