EZH2 Is Overexpressed in BRCA1-like Breast Tumors and Predictive for Sensitivity to High-Dose Platinum-Based Chemotherapy

Abstract

Purpose: BRCA1-deficient breast cancers carry a specific DNA copy-number signature ("BRCA1-like") and are hypersensitive to DNA double-strand break (DSB) inducing compounds. Here, we explored whether (i) EZH2 is overexpressed in human BRCA1-deficient breast tumors and might predict sensitivity to DSB-inducing drugs; (ii) EZH2 inhibition potentiates cisplatin efficacy in Brca1-deficient murine mammary tumors. Experimental Design: EZH2 expression was analyzed in 497 breast cancers using IHC or RNA sequencing. We classified 370 tumors by copy-number profiles as BRCA1-like or non-BRCA1-like and examined its association with EZH2 expression. Additionally, we assessed BRCA1 loss through mutation or promoter methylation status and investigated the predictive value of EZH2 expression in a study population of breast cancer patients treated with adjuvant high-dose platinumbased chemotherapy compared with standard anthracyclinebased chemotherapy. To explore whether EZH2 inhibition by GSK126 enhances sensitivity to platinum drugs in EZH2-overexpressing breast cancers we used a Brca1-deficient mouse model. Results: The highest EZH2 expression was found in BRCA1associated tumors harboring a BRCA1 mutation, BRCA1-promoter methylation or were classified as BRCA1 like. We observed a greater benefit from high-dose platinum-based chemotherapy in BRCA1-like and non-BRCA1-like patients with high EZH2 expression. Combined treatment with the EZH2 inhibitor GSK126 and cisplatin decreased cell proliferation and improved survival in Brca1-deficient mice in comparison with single agents. Conclusions: Our findings demonstrate that EZH2 is expressed at significantly higher levels in BRCA1-deficient breast cancers. EZH2 overexpression can identify patients with breast cancer who benefit significantly from intensified DSB-inducing platinum-based chemotherapy independent of BRCA1-like status. EZH2 inhibition improves the antitumor effect of platinum drugs in Brca1-deficient breast tumors in vivo.

MiR-33a functions as a tumor suppressor in triple-negative breast cancer by targeting EZH2

“…Tazemetostat, an EZH2 inhibitor, has been approved for treating epithelioid sarcoma, and it is the first EZH2 inhibitor approved by FDA [47]. Other EZH2 inhibitor, GSK343 and GSK236, were also reported to inhibit tumor progression in various cancer, such as glioblastoma [48], head and neck cancer, [49] and breast cancer [50]. Our in vitro study confirmed the regulatory mechanism of miR-33a/EZH2 cascade in TNBC progression, thus, more investigation of the effects of miR-33a and EZH2 on tumor growth and metastasis in vivo is needed.…”

Maximizing Breast Cancer Therapy with Awareness of Potential Treatment-Related Blood Disorders

“…Loss of BRCA activity can occur by somatic or germline mutation, loss of heterozygosity, copy number alterations (regional or whole chromosome alterations or deletions), or promoter methylation with gene silencing [59,60]. Multiple investigators have demonstrated that BRCA gene silencing via hypermethylation occurs not only in AML but also in multiple solid tumors, including breast, ovary, and prostate cancer [56,57,[59][60][61][62][63][64]. In addition, hypermethylation has been reported as a consequence of both cytotoxic chemotherapy and radiation [58].…”

EZH2 has a non-catalytic and PRC2-independent role in stabilizing DDB2 to promote nucleotide excision repair

“…EZH2 is the catalytic subunit of the PRC2, which functions together with Embryonic Ectoderm Development (EED) and Suppressor of Zeste 12 (SUZ12) as a histone methyltransferase to silence areas of active transcription through H3K27me3. EZH2 is an oncogene that is overexpressed in many cancer types, including SCLC [ 9 - 11 ], and high EZH2 expression is correlated with tumorigenesis, cancer progression, metastasis, and poor prognoses [ 10 , 12 - 19 ]. As such, EZH2 has emerged as an important therapeutic target.…”

“…A role for EZH2 in genome maintenance has previously been described. EZH2 has been reported to mediate resistance to DNA damaging agents, including etoposide in SCLC [ 34 - 37 ] and cisplatin in several other cancer cell types [ 9 , 38 - 41 ], localize to DNA damage sites [ 42 , 43 ], and promote DNA double-strand break (DSB) repair [ 42 , 44 ], degradation of stalled replication forks [ 45 ], and checkpoint signaling [ 46 ]; however, these functions have largely been attributed to H3K27Me3, either through transcriptional repression or a recently-described function for H3K27Me3 in the recruitment of MUS81 [ 45 ]. Significantly, a role for EZH2 in promoting NER, as well as in promoting genome maintenance independent of its catalytic activity or PRC2, has previously not been shown.…”