Estrogen receptor alpha (ERα) is a ligand-activated nuclear receptor that directs proliferation and differentiation in selected cancer cell types including mammary-derived carcinomas. These master-regulatory functions of ERα require trans-acting elements such as the pioneer factor FOXA1 to establish a genomic landscape conducive to ERα control. Here, we identify the H3K4 methyltransferase KMT2C as necessary for hormone-driven ERα activity and breast cancer proliferation. KMT2C knockdown suppresses estrogen-dependent gene expression and causes H3K4me1 and H3K27ac loss selectively at ERα enhancers. Correspondingly, KMT2C loss impairs estrogen-driven breast cancer proliferation but has no effect on ER- breast cells. Whereas KMT2C loss disrupts estrogen-driven proliferation, it conversely promotes tumor outgrowth under hormone-depleted conditions. In accordance, KMT2C is one of the most frequently mutated genes in ER-positive breast cancer with KMT2C deletion correlating with significantly shorter progression-free survival on anti-estrogen therapy. From a therapeutic standpoint, KMT2C-depleted cells that develop hormone-independence retain their dependence on ERα, displaying ongoing sensitivity to ERα antagonists. We conclude that KMT2C is a key regulator of ERα activity whose loss uncouples breast cancer proliferation from hormone abundance.

中文翻译：

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KMT2C 通过调节 ERα 增强子功能介导乳腺癌的雌激素依赖性。

雌激素受体α (ERα) 是一种配体激活的核受体，可在选定的癌细胞类型（包括乳腺癌）中指导增殖和分化。ERα 的这些主要调节功能需要诸如先锋因子 FOXA1 之类的反式作用元件来建立有利于 ERα 控制的基因组景观。在这里，我们确定 H3K4 甲基转移酶 KMT2C 是激素驱动的 ERα 活性和乳腺癌增殖所必需的。KMT2C 敲低抑制雌激素依赖性基因表达并导致 H3K4me1 和 H3K27ac 在 ERα 增强子处选择性丢失。相应地，KMT2C 缺失会损害雌激素驱动的乳腺癌增殖，但对 ER 乳腺细胞没有影响。尽管 KMT2C 缺失会破坏雌激素驱动的增殖，但它会在激素耗尽的条件下反过来促进肿瘤的生长。因此，KMT2C 是 ER 阳性乳腺癌中最常见的突变基因之一，KMT2C 缺失与抗雌激素治疗的无进展生存期显着缩短相关。从治疗的角度来看，KMT2C 耗竭的细胞会产生激素独立性，但仍依赖于 ERα，对 ERα 拮抗剂表现出持续的敏感性。我们得出结论，KMT2C 是 ERα 活性的关键调节剂，其丧失使乳腺癌增殖与激素丰度脱钩。显示对 ERα 拮抗剂的持续敏感性。我们得出结论，KMT2C 是 ERα 活性的关键调节剂，其丧失使乳腺癌增殖与激素丰度脱钩。显示对 ERα 拮抗剂的持续敏感性。我们得出结论，KMT2C 是 ERα 活性的关键调节剂，其丧失使乳腺癌增殖与激素丰度脱钩。