Role of the histone modifier MLL3 mutation in breast cancer cell plasticity

在人类癌症中发现表观遗传调节子的频繁体细胞突变 强调了表观遗传失调在癌症发病机制中的核心作用。然而， 这些突变的功能和作用机制在很大程度上仍不清楚。组蛋白 甲基转移酶MLL3(也称为KMT2C)是最常见的表观遗传学突变 调节因子在乳腺癌中也经常改变，在其他主要癌症中也经常改变。MLL3的大部分人 乳腺癌中的突变是基因缺失或蛋白质截短点突变。此外, 与正常乳腺组织相比，乳腺癌中MLL3的表达下调， 这表明它具有抑制肿瘤的作用。我们和其他人最近的功能研究 研究表明，MLL3在不同的癌症中是一种重要的肿瘤抑制因子。然而， MLL3突变驱动癌症发病的机制仍然知之甚少。 使用使用乳腺干细胞(MASC)和CRISPR的新肿瘤模型 技术，我们已经证明了MLL3的缺失会导致干细胞的扩张和驱动 PI3K突变与乳腺肿瘤的发生有关，PI3K突变与 乳腺癌中的MLL3突变。我们的初步数据还发现，MLL3突变破坏了 乳腺上皮细胞动态平衡与诱导多能干细胞活性 上皮细胞。此外，我们发现MLL3缺失致敏的细胞经历了上皮细胞- 间质转化(EMT)在对各种刺激的反应中。这些数据表明， MLL3突变在促进肿瘤细胞可塑性中的作用。EMT及其相关的细胞可塑性 在肿瘤的进展/转移和治疗耐药中起重要作用。始终如一， 我们发现MLL3缺失极大地促进了肿瘤转移和对内分泌治疗的抵抗 体内抑制PI3K活性。 基于这些新的发现，我们假设MLL3突变诱导上皮细胞 可塑性促进肿瘤的发生和转移，并对癌症治疗产生抵抗力。 我们将确定MLL3在组织过程中调节乳腺上皮细胞可塑性的作用 动态平衡和致癌转化(目标1)，区分MLL3的作用 甲基转移酶和适配器在EMT和肿瘤发生中的作用(目标2)，并确定 细胞可塑性在MLL3突变引起的治疗耐药中的作用(目标3)。

The discovery of frequent somatic mutations of epigenetic regulators in human cancers has highlighted a central role of epigenetic dysregulation in cancer pathogenesis. However, functions and mechanisms of action of these mutations remain largely unclear. The histone methyltransferase MLL3 (also known as KMT2C) is the most frequently mutated epigenetic regulator in breast cancer and also often altered in other major carcinomas. The majority of MLL3 mutations in breast cancer are gene deletion or protein-truncating point mutations. In addition, MLL3 expression is downregulated in breast cancers compared to normal breast tissues, suggesting it has a tumor suppressive role. Recent functional studies by us and others indeed have shown that MLL3 is an important tumor suppressor in different cancers. However, the mechanisms by which MLL3 mutations drive cancer pathogenesis remain poorly understood. Using novel tumor models that employ mammary stem cell (MaSC) and CRISPR technologies, we have shown that MLL3 deletion causes stem cell expansion and drives mammary tumorigenesis in cooperation with PI3K mutations, which significantly co-occur with MLL3 mutations in breast cancer. Our preliminary data also found that MLL3 mutation disrupted mammary epithelium homeostasis and induced multipotent stem cell activities in committed epithelial cell. Furthermore, we found MLL3 deletion sensitized cells to undergo epithelial- mesenchymal transition (EMT) in responding to various stimuli. These data suggest a role of MLL3 mutations in promoting cell plasticity in cancer development. EMT and related cell plasticity plays important role in cancer progression / metastasis and in therapeutic resistance. Consistently, we found MLL3 deletion greatly promoted tumor metastasis and resistance to endocrine therapy and PI3K inhibition in vivo. Based on these novel findings, we hypothesize that MLL3 mutation induces epithelial cell plasticity to promote tumorigenesis and metastasis and to confer resistance to cancer therapy. We will determine the role of MLL3 in regulating mammary epithelial cell plasticity during tissue homeostasis and oncogenic transformation (Aim 1), distinguish the role of MLL3 methyltransferase and adaptor functions in EMT and tumorigenesis (Aim 2), and determine the role of cell plasticity in MLL3 mutation-caused therapeutic resistance (Aim 3).