Intratumoral heterogeneity impacts the response to anti-neu antibody therapy

Hyunkeun Song; Tae O. Kim; Sun Y. Ma; Jin Hee Park; Jae Hyug Choi; Jin Ho Kim; Mi S. Kang; Sang K. Bae; Ki H. Kim; Tae H. Kim; Su Kil Seo; Il W. Choi; Geun A. Song; Eric D. Mortenson; Yang Xin Fu; Sae Gwang Park

doi:10.1186/1471-2407-14-647

Intratumoral heterogeneity impacts the response to anti-neu antibody therapy

Hyunkeun Song, Tae O. Kim, Sun Y. Ma, Jin Hee Park, Jae Hyug Choi, Jin Ho Kim, Mi S. Kang, Sang K. Bae, Ki H. Kim, Tae H. Kim, Su Kil Seo, Il W. Choi, Geun A. Song, Eric D. Mortenson, Yang Xin Fu, Sae Gwang Park

Research output: Contribution to journal › Article › peer-review

17 Scopus citations

Abstract

Background: Along with de novo resistance, continued exposure to trastuzumab, an anti-human epidermal growth factor receptor 2 (HER2/neu) antibody, can lead to acquired resistance. In this study, we characterize a new anti-HER2/neu antibody resistant and metastatic mouse breast carcinoma cell line, TUBO-P2J. This cell line was developed during in vivo experiments using the antibody sensitive and non-metastatic tumor line TUBO. In addition, TUBO-P2J was used to establish an intratumoral HER2 heterogenous animal tumor model to evaluate the therapeutic effects of anti-HER2/neu antibody.Methods: After establishing the cell line, TUBO-P2J was characterized regarding its susceptibility to anti-neu antibody and chemotherapeutics, as well as its metastatic potential in vitro and in vivo. In addition, expression profiles of metastasis related genes were also evaluated. A clinically relevant intratumoral HER2 heterogenous tumor model was established by inoculating mice with tumor cells consisting of TUBO and TUBO-P2J at a ratio of 1,000:1 or 10,000:1. Tumor growth and mouse survival were used to evaluate the therapeutic effects of anti-neu antibody.Results: The TUBO-P2J cell line is a HER2/neu negative and highly metastatic variant of TUBO. This cell line was resistant to anti-neu antibody therapy, and when inoculated subcutaneously, metastasized to the lungs within 14 days. Compared to the parental TUBO cell line, TUBO-P2J displayed an epithelial-mesenchymal transition (EMT) related gene expression profile including: the loss of E-cadherin, and increased Vimentin, Snail, and Twist1 expression. In addition, TUBO-P2J exhibited increased invasion and migration activity, and was resistant to chemotherapy drugs. Finally, mixed tumor implantations experiments revealed that an increased percentage of TUBO-P2J rendered tumors less responsive to anti-neu antibody therapy.Conclusion: This study describes a novel model of intratumoral heterogenous metastatic breast cancer in immune competent mice that can be used to develop novel or combined immunotherapies to overcome antibody resistance.

Original language	English (US)
Article number	647
Journal	BMC Cancer
Volume	14
Issue number	1
DOIs	https://doi.org/10.1186/1471-2407-14-647
State	Published - Sep 1 2014

Keywords

Animal model
Anti-HER2/neu antibody
Antibody resistance
Breast cancer
Epithelial mesenchymal transition
Intratumoral heterogeneity
Spontaneous metastasis

ASJC Scopus subject areas

Oncology
Genetics
Cancer Research

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10.1186/1471-2407-14-647

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@article{e18f6dd8dce9473da821c549cf953eb3,

title = "Intratumoral heterogeneity impacts the response to anti-neu antibody therapy",

abstract = "Background: Along with de novo resistance, continued exposure to trastuzumab, an anti-human epidermal growth factor receptor 2 (HER2/neu) antibody, can lead to acquired resistance. In this study, we characterize a new anti-HER2/neu antibody resistant and metastatic mouse breast carcinoma cell line, TUBO-P2J. This cell line was developed during in vivo experiments using the antibody sensitive and non-metastatic tumor line TUBO. In addition, TUBO-P2J was used to establish an intratumoral HER2 heterogenous animal tumor model to evaluate the therapeutic effects of anti-HER2/neu antibody.Methods: After establishing the cell line, TUBO-P2J was characterized regarding its susceptibility to anti-neu antibody and chemotherapeutics, as well as its metastatic potential in vitro and in vivo. In addition, expression profiles of metastasis related genes were also evaluated. A clinically relevant intratumoral HER2 heterogenous tumor model was established by inoculating mice with tumor cells consisting of TUBO and TUBO-P2J at a ratio of 1,000:1 or 10,000:1. Tumor growth and mouse survival were used to evaluate the therapeutic effects of anti-neu antibody.Results: The TUBO-P2J cell line is a HER2/neu negative and highly metastatic variant of TUBO. This cell line was resistant to anti-neu antibody therapy, and when inoculated subcutaneously, metastasized to the lungs within 14 days. Compared to the parental TUBO cell line, TUBO-P2J displayed an epithelial-mesenchymal transition (EMT) related gene expression profile including: the loss of E-cadherin, and increased Vimentin, Snail, and Twist1 expression. In addition, TUBO-P2J exhibited increased invasion and migration activity, and was resistant to chemotherapy drugs. Finally, mixed tumor implantations experiments revealed that an increased percentage of TUBO-P2J rendered tumors less responsive to anti-neu antibody therapy.Conclusion: This study describes a novel model of intratumoral heterogenous metastatic breast cancer in immune competent mice that can be used to develop novel or combined immunotherapies to overcome antibody resistance.",

keywords = "Animal model, Anti-HER2/neu antibody, Antibody resistance, Breast cancer, Epithelial mesenchymal transition, Intratumoral heterogeneity, Spontaneous metastasis",

author = "Hyunkeun Song and Kim, {Tae O.} and Ma, {Sun Y.} and Park, {Jin Hee} and Choi, {Jae Hyug} and Kim, {Jin Ho} and Kang, {Mi S.} and Bae, {Sang K.} and Kim, {Ki H.} and Kim, {Tae H.} and Seo, {Su Kil} and Choi, {Il W.} and Song, {Geun A.} and Mortenson, {Eric D.} and Fu, {Yang Xin} and Park, {Sae Gwang}",

note = "Publisher Copyright: {\textcopyright} 2014 Song et al.; licensee BioMed Central Ltd.",

year = "2014",

month = sep,

day = "1",

doi = "10.1186/1471-2407-14-647",

language = "English (US)",

volume = "14",

journal = "BMC Cancer",

issn = "1471-2407",

publisher = "BioMed Central",

number = "1",

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TY - JOUR

T1 - Intratumoral heterogeneity impacts the response to anti-neu antibody therapy

AU - Song, Hyunkeun

AU - Kim, Tae O.

AU - Ma, Sun Y.

AU - Park, Jin Hee

AU - Choi, Jae Hyug

AU - Kim, Jin Ho

AU - Kang, Mi S.

AU - Bae, Sang K.

AU - Kim, Ki H.

AU - Kim, Tae H.

AU - Seo, Su Kil

AU - Choi, Il W.

AU - Song, Geun A.

AU - Mortenson, Eric D.

AU - Fu, Yang Xin

AU - Park, Sae Gwang

PY - 2014/9/1

Y1 - 2014/9/1

N2 - Background: Along with de novo resistance, continued exposure to trastuzumab, an anti-human epidermal growth factor receptor 2 (HER2/neu) antibody, can lead to acquired resistance. In this study, we characterize a new anti-HER2/neu antibody resistant and metastatic mouse breast carcinoma cell line, TUBO-P2J. This cell line was developed during in vivo experiments using the antibody sensitive and non-metastatic tumor line TUBO. In addition, TUBO-P2J was used to establish an intratumoral HER2 heterogenous animal tumor model to evaluate the therapeutic effects of anti-HER2/neu antibody.Methods: After establishing the cell line, TUBO-P2J was characterized regarding its susceptibility to anti-neu antibody and chemotherapeutics, as well as its metastatic potential in vitro and in vivo. In addition, expression profiles of metastasis related genes were also evaluated. A clinically relevant intratumoral HER2 heterogenous tumor model was established by inoculating mice with tumor cells consisting of TUBO and TUBO-P2J at a ratio of 1,000:1 or 10,000:1. Tumor growth and mouse survival were used to evaluate the therapeutic effects of anti-neu antibody.Results: The TUBO-P2J cell line is a HER2/neu negative and highly metastatic variant of TUBO. This cell line was resistant to anti-neu antibody therapy, and when inoculated subcutaneously, metastasized to the lungs within 14 days. Compared to the parental TUBO cell line, TUBO-P2J displayed an epithelial-mesenchymal transition (EMT) related gene expression profile including: the loss of E-cadherin, and increased Vimentin, Snail, and Twist1 expression. In addition, TUBO-P2J exhibited increased invasion and migration activity, and was resistant to chemotherapy drugs. Finally, mixed tumor implantations experiments revealed that an increased percentage of TUBO-P2J rendered tumors less responsive to anti-neu antibody therapy.Conclusion: This study describes a novel model of intratumoral heterogenous metastatic breast cancer in immune competent mice that can be used to develop novel or combined immunotherapies to overcome antibody resistance.

AB - Background: Along with de novo resistance, continued exposure to trastuzumab, an anti-human epidermal growth factor receptor 2 (HER2/neu) antibody, can lead to acquired resistance. In this study, we characterize a new anti-HER2/neu antibody resistant and metastatic mouse breast carcinoma cell line, TUBO-P2J. This cell line was developed during in vivo experiments using the antibody sensitive and non-metastatic tumor line TUBO. In addition, TUBO-P2J was used to establish an intratumoral HER2 heterogenous animal tumor model to evaluate the therapeutic effects of anti-HER2/neu antibody.Methods: After establishing the cell line, TUBO-P2J was characterized regarding its susceptibility to anti-neu antibody and chemotherapeutics, as well as its metastatic potential in vitro and in vivo. In addition, expression profiles of metastasis related genes were also evaluated. A clinically relevant intratumoral HER2 heterogenous tumor model was established by inoculating mice with tumor cells consisting of TUBO and TUBO-P2J at a ratio of 1,000:1 or 10,000:1. Tumor growth and mouse survival were used to evaluate the therapeutic effects of anti-neu antibody.Results: The TUBO-P2J cell line is a HER2/neu negative and highly metastatic variant of TUBO. This cell line was resistant to anti-neu antibody therapy, and when inoculated subcutaneously, metastasized to the lungs within 14 days. Compared to the parental TUBO cell line, TUBO-P2J displayed an epithelial-mesenchymal transition (EMT) related gene expression profile including: the loss of E-cadherin, and increased Vimentin, Snail, and Twist1 expression. In addition, TUBO-P2J exhibited increased invasion and migration activity, and was resistant to chemotherapy drugs. Finally, mixed tumor implantations experiments revealed that an increased percentage of TUBO-P2J rendered tumors less responsive to anti-neu antibody therapy.Conclusion: This study describes a novel model of intratumoral heterogenous metastatic breast cancer in immune competent mice that can be used to develop novel or combined immunotherapies to overcome antibody resistance.

KW - Animal model

KW - Anti-HER2/neu antibody

KW - Antibody resistance

KW - Breast cancer

KW - Epithelial mesenchymal transition

KW - Intratumoral heterogeneity

KW - Spontaneous metastasis

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JO - BMC Cancer

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Intratumoral heterogeneity impacts the response to anti-neu antibody therapy

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