Association of H3K9me3 and H3K27me3 repressive histone marks with breast cancer subtypes in the Nurses’ Health Study

Abstract

Repressive histone tail modifications have been associated with molecular breast cancer subtypes. We investigated whether histone 3 lysine 9 trimethylation (H3K9me3) and histone 3 lysine 27 trimethylation (H3K27me3) were associated with tumor features and subtypes while adjusting for prospectively collected reproductive and lifestyle breast cancer risk factors. We have tissue microarray data with immunohistochemical marker information on 804 incident cases of invasive breast cancer diagnosed from 1976-2000 in the Nurses' Health Study. Tissue microarray sections were stained for global H3K9me3 and H3K27me3, and scored into four categories. Multivariate odds ratios (OR) and 95 % confidence intervals (CI) were calculated using logistic regression models for tumor features and subtypes, adjusting for breast cancer risk factors. While there were no significant associations between H3K9me3 and tumor features, H3K27me3 was significantly associated with lower grade tumors compared to high grade tumors in the multivariate model (OR = 1.95, 95 % CI 1.35-2.81, p = 0.0004). H3K27me3 was suggestively associated with estrogen receptor-positive (ER+) tumors (OR = 1.47, 95 % CI 0.97-2.23, p = 0.07). In subtype analyses, H3K27me3 was positively associated with the luminal A subtype compared to all other subtypes (OR = 1.42, 95 % CI 1.14-1.77, p = 0.002), and was inversely associated with HER2-type (OR = 0.58, 95 % CI 0.37-0.91, p = 0.02) and basal-like breast cancer (OR = 0.52, 95 % CI 0.36-0.76, p = 0.0006). In the largest immunohistochemical examination of H3K9me3 and H3K27me3 in breast cancer, we found that H3K27me3 positivity, but not H3K9me3, was associated with lower grade tumors and the luminal A subtype after adjusting for reproductive and lifestyle breast cancer risk factors.

Impaired PRC2 activity promotes transcriptional instability and favors breast tumorigenesis

“…Thus, PRC2 activity might not be sufficient to maintain the mark in rapidly dividing breast cancer cells. We propose that these observations reconcile contradictory data reporting inverse variations of EZH2 and H3K27me3 in several tumor types (Wei et al 2008;Holm et al 2012;Xu et al 2012;Healey et al 2014;Bae et al 2015).…”

“…Paradoxically, recent studies have reported that the levels of H3K27me3 are decreased in several solid tumor types, including breast and prostate (Wei et al 2008;Holm et al 2012;Xu et al 2012;Healey et al 2014;Bae et al 2015). Even more surprising, the levels of the enzyme and the mark were found to be anti-correlated between the different breast cancer subtypes (Holm et al 2012), and, while high expression of EZH2 correlates with poor prognosis, high levels of H3K27me3 correlate with good prognosis (Holm et al 2012;Bae et al 2015).…”

Epigenetics of Breast Cancer: DNA Methylome and Global Histone Modifications

“…There was an inverse correlation between H3K27me3 and EZH2 expression in different tumor types and tumor grades as high expression of EZH2 was associated with high grades and ER(−)/PR(−) tumors and these tumors were observed to have low H3K27me3 levels [ 75 ]. Consistent with this study, examination of H3K27me3 on tissue micro arrays in the Nurses' Health Study demonstrated a signifi cant association of H3K27me3 mark with lower tumor grade and a positive association with ER(+) and PR(+) tumors [ 68 ]. Finally, H3K27me3 was also observed to be positively associated with luminal subtype A breast cancers [ 68 , 75 ].…”

HIFI-α activation underlies a functional switch in the paradoxical role of Ezh2/PRC2 in breast cancer

“…Moreover, high-grade breast, ovarian, and pancreatic cancers have been found to harbor low global H3K27me3, which is correlated with increased recurrence and poor survival (19)(20)(21). Particularly in breast cancer, EZH2 and H3K27me3 levels are found to be not correlated across different subtypes, with higher expression of EZH2 in basal-like/TNBC and HER2 + tumors, and high H3K27me3 level in luminal A, luminal B, and normal-like tumors (19,22). Consequently, a high EZH2 expression is associated with poor disease outcome (19,20,23), and a high H3K27me3 level is associated with better outcome (19,20,22).…”

“…Particularly in breast cancer, EZH2 and H3K27me3 levels are found to be not correlated across different subtypes, with higher expression of EZH2 in basal-like/TNBC and HER2 + tumors, and high H3K27me3 level in luminal A, luminal B, and normal-like tumors (19,22). Consequently, a high EZH2 expression is associated with poor disease outcome (19,20,23), and a high H3K27me3 level is associated with better outcome (19,20,22). Thus, the oncogenic function of Ezh2 in TNBC is not well coupled with the H3K27me3 level; instead, it might be more connected to its nonepigenetic silencing effect.…”