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Open Access Highly Accessed Research article

Intratumoral heterogeneity impacts the response to anti-neu antibody therapy

Hyunkeun Song1, Tae Oh Kim2, Sun Young Ma3, Jin-Hee Park1, Jae-Hyug Choi1, Jin-Ho Kim1, Mi Seon Kang4, Sang Kyun Bae5, Ki Hyaung Kim5, Tae Hyun Kim6, Su-Kil Seo1, Il Whan Choi1, Geun Am Song7, Eric D Mortenson8, Yang-Xin Fu9* and SaeGwang Park1*

Author Affiliations

1 Departmentof Microbiology and Immunology, INJE University College of Medicine, 633-165 GaegumDong, Busanjin Gu, Busan 614-735, Republic of Korea

2 Department of Internal Medicine, Haeundae Paik Hospital, INJE University College of Medicine, Busan, Republic of Korea

3 Department of Radiation Oncology, Kosin University College of Medicine, Busan 602-702, Republic of Korea

4 Departmentof Pathology, INJE University College of Medicine, Busan 614-735, Republic of Korea

5 Department of Nuclear Medicine, INJE University College of Medicine, Busan 614-735, Republic of Korea

6 Department of Surgery, INJE University College of Medicine, Busan 614-735, Republic of Korea

7 Departmentof Internal Medicine, Pusan National University School of Medicine, Busan, Republic of Korea

8 Department of Melanoma Medical Oncology-Research, MD Anderson Cancer Center, Houston, TX 77054, USA

9 Departmentof Pathology and Committee on Immunology, University of Chicago, 924 E. 57thStreet, BSLC R102, Chicago, IL 60637, USA

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BMC Cancer 2014, 14:647  doi:10.1186/1471-2407-14-647

Published: 1 September 2014

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