DMBA induced mouse mammary tumors display high incidence of activating Pik3caH1047 and loss of function Pten mutations

Autores
Abba, Martín Carlos; Zhong, Yi; Lee, Jaeho; Kil, Hyunsuk; Lu, Yue; Takata, Yoko; Simper, Melissa S.; Gaddis, Sally; Shen, Jianjun; Aldaz, Claudio Marcelo
Año de publicación
2016
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
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.
Fil: Abba, Martín Carlos. Universidad Abierta Interamericana. Facultad de Tecnología Informatica; Argentina. Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Centro de Investigaciones Inmunológicas Básicas y Aplicadas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Zhong, Yi. University of Texas; Estados Unidos
Fil: Lee, Jaeho. University of Texas; Estados Unidos
Fil: Kil, Hyunsuk. University of Texas; Estados Unidos
Fil: Lu, Yue. University of Texas; Estados Unidos
Fil: Takata, Yoko. University of Texas; Estados Unidos
Fil: Simper, Melissa S.. University of Texas; Estados Unidos
Fil: Gaddis, Sally. University of Texas; Estados Unidos
Fil: Shen, Jianjun. University of Texas; Estados Unidos
Fil: Aldaz, Claudio Marcelo. University of Texas; Estados Unidos
Materia
DMBA
MAMMARY TUMORS
MPA
PIK3CA
PTEN
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/54748
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/54748
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling DMBA induced mouse mammary tumors display high incidence of activating Pik3caH1047 and loss of function Pten mutationsAbba, Martín CarlosZhong, YiLee, JaehoKil, HyunsukLu, YueTakata, YokoSimper, Melissa S.Gaddis, SallyShen, JianjunAldaz, Claudio MarceloDMBAMAMMARY TUMORSMPAPIK3CAPTENhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Controversy 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.Fil: Abba, Martín Carlos. Universidad Abierta Interamericana. Facultad de Tecnología Informatica; Argentina. Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Centro de Investigaciones Inmunológicas Básicas y Aplicadas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Zhong, Yi. University of Texas; Estados UnidosFil: Lee, Jaeho. University of Texas; Estados UnidosFil: Kil, Hyunsuk. University of Texas; Estados UnidosFil: Lu, Yue. University of Texas; Estados UnidosFil: Takata, Yoko. University of Texas; Estados UnidosFil: Simper, Melissa S.. University of Texas; Estados UnidosFil: Gaddis, Sally. University of Texas; Estados UnidosFil: Shen, Jianjun. University of Texas; Estados UnidosFil: Aldaz, Claudio Marcelo. University of Texas; Estados UnidosImpact Journals2016-05info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/54748Abba, Martín Carlos; Zhong, Yi; Lee, Jaeho; Kil, Hyunsuk; Lu, Yue; et al.; DMBA induced mouse mammary tumors display high incidence of activating Pik3caH1047 and loss of function Pten mutations; Impact Journals; OncoTarget; 7; 39; 5-2016; 64289-642991949-2553CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.18632/oncotarget.11733info:eu-repo/semantics/altIdentifier/url/http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=11733&path[]=45149info:eu-repo/semantics/altIdentifier/url/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5325442/info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-29T11:57:53Zoai:ri.conicet.gov.ar:11336/54748instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-10-29 11:57:54.232CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv DMBA induced mouse mammary tumors display high incidence of activating Pik3caH1047 and loss of function Pten mutations
title DMBA induced mouse mammary tumors display high incidence of activating Pik3caH1047 and loss of function Pten mutations
spellingShingle DMBA induced mouse mammary tumors display high incidence of activating Pik3caH1047 and loss of function Pten mutations
Abba, Martín Carlos
DMBA
MAMMARY TUMORS
MPA
PIK3CA
PTEN
title_short DMBA induced mouse mammary tumors display high incidence of activating Pik3caH1047 and loss of function Pten mutations
title_full DMBA induced mouse mammary tumors display high incidence of activating Pik3caH1047 and loss of function Pten mutations
title_fullStr DMBA induced mouse mammary tumors display high incidence of activating Pik3caH1047 and loss of function Pten mutations
title_full_unstemmed DMBA induced mouse mammary tumors display high incidence of activating Pik3caH1047 and loss of function Pten mutations
title_sort DMBA induced mouse mammary tumors display high incidence of activating Pik3caH1047 and loss of function Pten mutations
dc.creator.none.fl_str_mv Abba, Martín Carlos
Zhong, Yi
Lee, Jaeho
Kil, Hyunsuk
Lu, Yue
Takata, Yoko
Simper, Melissa S.
Gaddis, Sally
Shen, Jianjun
Aldaz, Claudio Marcelo
author Abba, Martín Carlos
author_facet Abba, Martín Carlos
Zhong, Yi
Lee, Jaeho
Kil, Hyunsuk
Lu, Yue
Takata, Yoko
Simper, Melissa S.
Gaddis, Sally
Shen, Jianjun
Aldaz, Claudio Marcelo
author_role author
author2 Zhong, Yi
Lee, Jaeho
Kil, Hyunsuk
Lu, Yue
Takata, Yoko
Simper, Melissa S.
Gaddis, Sally
Shen, Jianjun
Aldaz, Claudio Marcelo
author2_role author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv DMBA
MAMMARY TUMORS
MPA
PIK3CA
PTEN
topic DMBA
MAMMARY TUMORS
MPA
PIK3CA
PTEN
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv 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.
Fil: Abba, Martín Carlos. Universidad Abierta Interamericana. Facultad de Tecnología Informatica; Argentina. Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Centro de Investigaciones Inmunológicas Básicas y Aplicadas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Zhong, Yi. University of Texas; Estados Unidos
Fil: Lee, Jaeho. University of Texas; Estados Unidos
Fil: Kil, Hyunsuk. University of Texas; Estados Unidos
Fil: Lu, Yue. University of Texas; Estados Unidos
Fil: Takata, Yoko. University of Texas; Estados Unidos
Fil: Simper, Melissa S.. University of Texas; Estados Unidos
Fil: Gaddis, Sally. University of Texas; Estados Unidos
Fil: Shen, Jianjun. University of Texas; Estados Unidos
Fil: Aldaz, Claudio Marcelo. University of Texas; Estados Unidos
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 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.
publishDate 2016
dc.date.none.fl_str_mv 2016-05
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/54748
Abba, Martín Carlos; Zhong, Yi; Lee, Jaeho; Kil, Hyunsuk; Lu, Yue; et al.; DMBA induced mouse mammary tumors display high incidence of activating Pik3caH1047 and loss of function Pten mutations; Impact Journals; OncoTarget; 7; 39; 5-2016; 64289-64299
1949-2553
CONICET Digital
CONICET
url http://hdl.handle.net/11336/54748
identifier_str_mv Abba, Martín Carlos; Zhong, Yi; Lee, Jaeho; Kil, Hyunsuk; Lu, Yue; et al.; DMBA induced mouse mammary tumors display high incidence of activating Pik3caH1047 and loss of function Pten mutations; Impact Journals; OncoTarget; 7; 39; 5-2016; 64289-64299
1949-2553
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.18632/oncotarget.11733
info:eu-repo/semantics/altIdentifier/url/http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=11733&path[]=45149
info:eu-repo/semantics/altIdentifier/url/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5325442/
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Impact Journals
publisher.none.fl_str_mv Impact Journals
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.10058

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