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HER2 Heterogeneity Is Associated with Poor Survival in HER2-Positive Breast Cancer

1
Department of Breast Surgery and Oncology, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan
2
Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
3
Department of Genomic Pathology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
4
Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
5
Center for Supercentenarian Medical Research, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
6
Department of Pathology (Medical Research Center), Institute of Medical Science, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan
7
Laboratory of Gene Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2018, 19(8), 2158; https://doi.org/10.3390/ijms19082158
Received: 15 May 2018 / Revised: 13 July 2018 / Accepted: 20 July 2018 / Published: 24 July 2018
(This article belongs to the Special Issue Molecular Biology and Pathology of Breast Cancer)
Intratumoral human epidermal growth factor receptor 2 (HER2) heterogeneity has been reported in 16–36% of HER2-positive breast cancer and its clinical impact is under discussion. We examined the biological effects of HER2-heterogeneity on mouse models and analyzed metastatic brains by RNA sequence analysis. A metastatic mouse model was developed using 231-Luc (triple negative cells) and 2 HER2-positive cell lines, namely, HER2-60 and HER2-90 which showed heterogeneous and monotonous HER2 expressions, respectively. Metastatic lesions developed in 3 weeks in all the mice injected with HER2-60 cells, and in 69% of the mice injected with HER2-90 and 87.5% of the mice injected with 231-Luc. The median survival days of mice injected with 231-Luc, HER2-60, and HER2-90 cells were 29 (n = 24), 24 (n = 22) and 30 (n = 13) days, respectively. RNA sequence analysis showed that CASP-1 and its related genes were significantly downregulated in metastatic brain tumors with HER2-60 cells. The low expression of caspase-1 could be a new prognostic biomarker for early relapse in HER2-positive breast cancer. View Full-Text
Keywords: HER2; heterogeneity; breast cancer; poor prognosis; caspase-1 HER2; heterogeneity; breast cancer; poor prognosis; caspase-1
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Hosonaga, M.; Arima, Y.; Sampetrean, O.; Komura, D.; Koya, I.; Sasaki, T.; Sato, E.; Okano, H.; Kudoh, J.; Ishikawa, S.; Saya, H.; Ishikawa, T. HER2 Heterogeneity Is Associated with Poor Survival in HER2-Positive Breast Cancer. Int. J. Mol. Sci. 2018, 19, 2158.

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