Association of H3K9me3 with breast cancer prognosis by estrogen receptor status

Abstract

Background: Cellular experiments revealed that a decreased histone H3 lysine 9 trimethylation (H3K9me3) level was associated with the upregulation of oncogenes in breast cancer cells. Moreover, the role of H3K9me3 in breast cancer was closely associated with estrogen receptor (ER) status. Therefore, we aimed to examine the prognostic value of H3K9me3 on breast cancer by ER status. The level of H3K9me3 in tumors were evaluated with tissue microarrays by immunohistochemistry for 917 women diagnosed with primary invasive breast cancer. Hazard ratios (HRs) and their 95% confidence intervals (CIs) for overall survival (OS) and progression-free survival (PFS) were estimated using Cox regression models. Interaction between H3K9me3 and ER on the prognosis was assessed on multiplicative scale.

Results: The level of H3K9me3 in tumor tissues was lower than that in adjacent tissues. The high level of H3K9me3 was associated with a better OS (HR = 0.43, 95% CI: 0.21-0.86) and PFS (HR = 0.49, 95% CI: 0.29-0.81) among only ER-positive but not ER-negative tumors. Moreover, the interaction between the level of H3K9me3 and ER status (negative and positive) on the prognosis was significant (P_interaction = 0.011 for OS; P_interaction = 0.022 for PFS). Furthermore, the ER-positive tumors were stratified by ER-low and ER-high positive tumors, and the prognostic role of H3K9me3 was significant among only ER-high positive patients (HR = 0.34, 95% CI: 0.13-0.85 for OS; HR = 0.47, 95% CI: 0.26-0.86 for PFS).

Conclusions: Our study showed that the prognostic value of H3K9me3 on breast cancer was related to ER status and expression level, and the high level of H3K9me3 was associated with a better prognosis among ER-positive tumors, particularly ER-high positive tumors.

Keywords: Breast cancer; Estrogen receptor; H3K9me3; Prognosis.