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. 2018 Jul 24;19(8):2158.
doi: 10.3390/ijms19082158.

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

Mari Hosonaga  1 , Yoshimi Arima  2 , Oltea Sampetrean  3 , Daisuke Komura  4 , Ikuko Koya  5 , Takashi Sasaki  6 , Eiichi Sato  7 , Hideyuki Okano  8 , Jun Kudoh  9 , Shumpei Ishikawa  10 , Hideyuki Saya  11 , Takashi Ishikawa  12
Affiliations

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

Mari Hosonaga et al. Int J Mol Sci. .

Abstract

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.

Keywords: HER2; breast cancer; caspase-1; heterogeneity; poor prognosis.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Heterogeneous HER2 expression is associated with a short survival time in metastatic breast cancer. (a–f) Representative bioluminescence images of mice after intracardiac injection (upper panel). H&E staining of formalin-fixed, paraffin-embedded metastasized brain sections. Scale bar, 250 μm (lower panel). (a,b) Injected with 231-Luc cells; (c,d) injected with HER2-60 cells; (e,f) injected with HER2-90 cells; (g) survival curves of mice after intracardiac injection of 231-Luc (n = 24), HER2-60 (n = 22), and HER2-90 (n = 13) cells (231-Luc vs. HER2-60; p < 0.001; 231-Luc vs. HER2-90; p = 0.34).
Figure 2
Figure 2
The expression levels of caspase-1 and its related genes were decreased in the metastatic brain with HER2-60 cells. (a) mRNA levels of caspase-1-related genes of cancer cells in the metastatic brains with 231-Luc, HER2-60, and HER2-90 cells. The values are shown in Table 1; (b,c) relative mRNA levels in the metastatic brains with HER2-60 cells compared with those with HER2-90 cells; (b) relative mRNA levels of cancer cells; (c) relative mRNA levels of mouse stromal cells. The values are shown in Table S6.
Figure 2
Figure 2
The expression levels of caspase-1 and its related genes were decreased in the metastatic brain with HER2-60 cells. (a) mRNA levels of caspase-1-related genes of cancer cells in the metastatic brains with 231-Luc, HER2-60, and HER2-90 cells. The values are shown in Table 1; (b,c) relative mRNA levels in the metastatic brains with HER2-60 cells compared with those with HER2-90 cells; (b) relative mRNA levels of cancer cells; (c) relative mRNA levels of mouse stromal cells. The values are shown in Table S6.
Figure 3
Figure 3
Heterogeneous HER2 expression is correlated with a high risk of relapse and resistance to chemotherapy plus trastuzumab in patients with HER2-positive breast cancer. (a) Representative IHC staining of HER2-mono tumors. Scale bar, 250 μm; (b) representative IHC staining of HER2-hetero tumors. Scale bar, 250 μm; (c) PCR rate of HER2-positive breast cancer patients treated with chemotherapy plus trastuzumab (p = 0.29); (d) Disease free survival (DFS) curves of patients with HER2-positive breast cancer after neoadjuvant chemotherapy plus surgery. The median DFS has not been reached (p = 0.97).
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References

    1. Gerlinger M., Rowan A.J., Horswell S., Larkin J., Stewart A., Tarpey P., Varela I. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N. Engl. J. Med. 2012;366:883–892. doi: 10.1056/NEJMoa1113205. - DOI - PMC - PubMed
    1. Shackleton M., Quintana E., Fearon E.R., Morrison S.J. Heterogeneity in cancer: Cancer stem cells versus clonal evolution. Cell. 2009;138:822–829. doi: 10.1016/j.cell.2009.08.017. - DOI - PubMed
    1. Huang S. Non-genetic heterogeneity of cells in development: More than just noise. Development. 2009;136:3853–3862. doi: 10.1242/dev.035139. - DOI - PMC - PubMed
    1. Shah S.P., Morin R.D., Khattra J., Prentice L., Pugh T., Burleigh A., Delaney A., Gelmon K., Guliany R., Senz J., et al. Mutational evolution in a lobular breast tumour profiled at single nucleotide resolution. Nature. 2009;461:809–813. doi: 10.1038/nature08489. - DOI - PubMed
    1. Park S.Y., Gonen M., Kim H.J., Michor F., Polyak K. Cellular and genetic diversity in the progression of in situ human breast carcinomas to an invasive phenotype. J. Clin. Investig. 2010;120:636–644. doi: 10.1172/JCI40724. - DOI - PMC - PubMed

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