Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry, "Scuola Medica Salernitana", University of Salerno, Baronissi, SA, Italy.
Genomix4Life Srl, University of Salerno, Baronissi, SA, Italy.
Sci Adv. 2019 Feb 6;5(2):eaav5590. doi: 10.1126/sciadv.aav5590. eCollection 2019 Feb.
Breast cancer (BC) resistance to endocrine therapy results from constitutively active or aberrant estrogen receptor α (ERα) signaling, and ways to block ERα pathway in these tumors are sought after. We identified the H3K79 methyltransferase DOT1L as a novel cofactor of ERα in BC cell chromatin, where the two proteins colocalize to regulate estrogen target gene transcription. DOT1L blockade reduces proliferation of hormone-responsive BC cells in vivo and in vitro, consequent to cell cycle arrest and apoptotic cell death, with widespread effects on ER-dependent gene transcription, including ERα and FOXA1 gene silencing. Antiestrogen-resistant BC cells respond to DOT1L inhibition also in mouse xenografts, with reduction in ERα levels, H3K79 methylation, and tumor growth. These results indicate that DOT1L is an exploitable epigenetic target for treatment of endocrine therapy-resistant ERα-positive BCs.
乳腺癌（BC）对内分泌治疗的耐药性源于组成型激活或异常的雌激素受体 α（ERα）信号，因此人们一直在寻找阻断这些肿瘤中 ERα 通路的方法。我们鉴定出 H3K79 甲基转移酶 DOT1L 是 BC 细胞染色质中 ERα 的一种新型共因子，这两种蛋白质在染色质中共定位以调节雌激素靶基因转录。DOT1L 阻断可减少激素反应性 BC 细胞在体内和体外的增殖，导致细胞周期停滞和细胞凋亡，同时广泛影响 ER 依赖性基因转录，包括 ERα 和 FOXA1 基因沉默。抗雌激素耐药的 BC 细胞在小鼠异种移植中也对 DOT1L 抑制有反应，表现为 ERα 水平、H3K79 甲基化和肿瘤生长减少。这些结果表明，DOT1L 是治疗内分泌治疗耐药性 ERα 阳性 BC 的一种可利用的表观遗传靶标。
