p53 drives epigenetic programs associated with luminal cell identity in breast cancer [ATAC-seq]

Breast cancer is one of the most commonly diagnosed cancers among women and the leading cause of death in women under 50. The majority of breast cancers are estrogen receptor a-positive (ER+). Historically, these cancers are treated with therapies, such as tamoxifen, that inhibit ER activity. The TP53 tumor suppressor gene, encoding the p53 protein, is the most frequently mutated gene in breast cancer, and TP53 mutations are associated with diminished tamoxifen response and worse prognosis. Here, we report that in breast cancer cells p53 and ER cooperate to regulate the expression of a set of genes encoding chromatin modifiers. The net result is a global increase in H3K4me3 and decrease in H3K9me3 chromatin marks. The resultant “open” chromatin is associated with increased transcription of luminal cell identity genes and augmented tamoxifen sensitivity. Conversely, diminished p53 control of these chromatin modulators is associated with the evolution of tamoxifen resistance and cancer stem cell properties. Overall design: ATACseq analysis of WT or p53 KO MCF7 cells treated with Tamoxifen

乳腺癌是女性中最常被确诊的癌症之一，同时也是50岁以下女性死亡的首要诱因。大多数乳腺癌为雌激素受体α阳性（estrogen receptor α-positive, ER+）型。既往针对此类癌症的治疗方案多采用他莫昔芬等可抑制ER活性的疗法。编码p53蛋白的TP53抑癌基因是乳腺癌中突变频率最高的基因，且TP53突变与他莫昔芬应答减弱及不良预后密切相关。本研究发现，在乳腺癌细胞中，p53与ER可协同调控一系列编码染色质调控因子的基因的表达。其最终结果是全基因组范围内H3K4me3修饰水平升高，而H3K9me3修饰水平降低。由此形成的“开放”染色质状态与管腔细胞特征基因的转录上调及他莫昔芬敏感性增强相关。反之，p53对这些染色质调控因子的调控功能受损，则会促进他莫昔芬耐药性的产生及癌症干细胞特性的获得。实验整体设计：对经他莫昔芬处理的野生型（wild type, WT）或p53敲除（knockout, KO）MCF7细胞进行ATAC-seq分析。