Department of Developmental Biology and Cancer Research, Institute for Medical Research – Israel-Canada, Hadassah School of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
Oncogene. 2013 Aug 15;32(33):3886-95. doi: 10.1038/onc.2012.390.
The mechanisms regulating breast cancer differentiation state are poorly understood. Of particular interest are molecular regulators controlling the highly aggressive and poorly differentiated traits of basal-like breast carcinomas. Here we show that the Polycomb factor EZH2 maintains the differentiation state of basal-like breast cancer cells, and promotes the expression of progenitor associated and basal-lineage genes. Specifically, EZH2 regulates the composition of basal-like breast cancer cell populations by promoting a ‘bi-lineage’ differentiation state, in which cells co-express basal- and luminal-lineage markers. We show that human basal-like breast cancers contain a subpopulation of bi-lineage cells, and that EZH2-deficient cells give rise to tumors with a decreased proportion of such cells. Bi-lineage cells express genes that are active in normal luminal progenitors, and possess increased colony-formation capacity, consistent with a primitive differentiation state. We found that GATA3, a driver of luminal differentiation, performs a function opposite to EZH2, acting to suppress bi-lineage identity and luminal-progenitor gene expression. GATA3 levels increase upon EZH2 silencing, mediating a decrease in bi-lineage cell numbers. Our findings reveal a novel role for EZH2 in controlling basal-like breast cancer differentiation state and intra-tumoral cell composition.
调控乳腺癌分化状态的机制尚不清楚。特别有趣的是，分子调控因子控制基底样乳腺癌的高度侵袭性和低分化特征。在这里，我们表明多梳抑制因子 EZH2 维持基底样乳腺癌细胞的分化状态，并促进祖细胞相关和基底谱系基因的表达。具体来说，EZH2 通过促进“双谱系”分化状态来调节基底样乳腺癌细胞群体的组成，其中细胞共同表达基底和腔系标记物。我们表明，人基底样乳腺癌包含一个双谱系细胞亚群，EZH2 缺陷细胞产生的肿瘤中这种细胞的比例降低。双谱系细胞表达在正常腔前体细胞中活跃的基因，并具有增加的集落形成能力，与原始分化状态一致。我们发现，GATA3 是腔分化的驱动因子，其功能与 EZH2 相反，可抑制双谱系特征和腔前体细胞基因的表达。EZH2 沉默后 GATA3 水平升高，导致双谱系细胞数量减少。我们的研究结果揭示了 EZH2 在控制基底样乳腺癌分化状态和肿瘤内细胞组成中的新作用。
