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Survival is associated with repressive histone trimethylation markers in both HR-positive HER2-negative and triple-negative breast cancer patients

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Abstract

About 30% of patients with hormone receptor (HR)-positive breast cancers and up to 50% of human epidermal growth factor receptor 2 (HER2)-positive patients develop progression due to treatment resistance, highlighting the need for more differentiated tumor classifications within the breast cancer molecular subtype to optimize the therapies. We aim to examine the roles of histone modification markers. The levels of common repressive histone markers, histone H3 lysine 9 trimethylation (H3K9me3), histone H3 lysine 27 trimethylation (H3K27me3), and histone H4 lysine 20 trimethylation (H4K20me3), in tumors were evaluated by immunohistochemistry for 914 breast cancer patients. The subjects were followed up until December 2021. Hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) were estimated using Cox regression models. For H3K27me3, patients with the high level had a longer PFS rate (81.3%) than that with the low level (73.9%) within HR-positive/HER2-negative subtype during a follow-up of 85 months only in univariate analysis (P < 0.05). For H3K9me3, the significant association between the high level of it and the longer OS [HR = 0.57, P < 0.05] was found within HR-positive/HER2-negative subtype in multivariate analysis. For H4K20me3, patients with the high level had a longer both OS [HR = 0.38] and PFS [HR = 0.46] within HR-positive/HER2-negative subtype, while had a shorter OS [HR = 3.28] in triple-negative breast cancer (TNBC) in multivariate analysis (all P < 0.05). H3K9me3 and H3K27me3 were the potential prognostic markers for breast cancer patients with HR-positive/HER2-negative subtype. Importantly, H4K20me3 was a robust prognostic marker for both HR-positive/HER2-negative and TNBC patients.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Code availability

The R code used during the current study is available from the corresponding author on reasonable request.

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Acknowledgements

We sincerely thank the patients who participated in this study, the staff who conducted the baseline and the follow-up data collection, and the medical staff in the breast departments of the Third Affiliated Hospital, and the Cancer Center of Sun Yat-sen University. We also sincerely thank National Natural Science Foundation of China (81973115) and Science and Technology Planning Project of Guangdong Province, China (2019B030316002).

Funding

This study was funded by National Natural Science Foundation of China (81973115) and Science and Technology Planning Project of Guangdong Province, China (2019B030316002). The founders have no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Authors and Affiliations

  1. School of Public Health, Sun Yat-Sen University, Guangzhou, 510080, China

    Bo Wang, Meng Zhou, Yue-yu Shi, Xing-lei Chen & Ze-fang Ren

  2. The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510630, China

    Yue-xiang Ren & Lu-ying Tang

  3. The Sun Yat-Sen University Cancer Center, Guangzhou, 510080, China

    Yuan-zhong Yang

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  1. Bo Wang
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Contributions

Bo Wang, Meng Zhou, and Ze-fang Ren designed and directed the study, wrote, and/or revised the manuscript. Yuan-zhong Yang constructed the TMAs and contributed to the IHC. Yue-xiang Ren and Lu-ying Tang contributed to digital imaging of IHC-stained sections and the assessment of immunohistochemical expression. Bo Wang, Meng Zhou, Yue-yu Shi, and Xing-lei Chen contributed to clinical data collection and curation. Bo Wang, Meng Zhou, Yue-yu Shi, and Xing-lei Chen participated in the statistical analysis plan and interpretation of results. Ze-fang Ren provided administrative support and supervision for the study. All authors approved the final manuscript.

Corresponding authors

Correspondence to Lu-ying Tang or Ze-fang Ren.

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Wang, B., Zhou, M., Shi, Yy. et al. Survival is associated with repressive histone trimethylation markers in both HR-positive HER2-negative and triple-negative breast cancer patients. Virchows Arch 482, 1047–1056 (2023). https://doi.org/10.1007/s00428-023-03534-5

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