ESR1 mutation profiling identifies potential drivers of metastatic breast cancer

ESR1 突变分析确定了转移性乳腺癌的潜在驱动因素

• 批准号: MR/X018199/1
• 负责人: Simak Ali
• 金额: $ 101.57万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FX018199%2F1
• 关键词: ESR1; mutation; profiling; identifies; potential

Breast cancer is the most common cancer in the world, being responsible for 1 in 4 cancer diagnoses and 1 in 6 cancer deaths in women every year. The female hormone estrogen promotes both breast cancer development and its progression. The estrogen receptor (ER) protein mediates the cellular actions of estrogen. Estrogen binding to ER is necessary for activation of the ER. The activated estrogen-bound ER protein stimulates breast cancer development by inducing expression of the genes that work together to drive breast cancer growth. The majority (>70%) of breast cancers are ER-positive and standard-of-care drug treatments for ER-positive breast cancer work by blocking ER activity. These "endocrine therapies" are proven, effective treatments for reducing illness and death from breast cancer. However, many patients relapse. Rates of recurrence, inevitably of endocrine therapy refractory metastatic disease, remain constant even several decades after original diagnosis and surgical removal of the tumour from the breast, necessitating the development of new treatments.Recent advances in DNA sequencing have revealed that the ER gene is mutated in up to 40% of patients whose tumours recur. These mutated ER proteins are constitutively active such that their activity is not blocked by endocrine therapies. Consequently, breast cancer patients with mutant ER cannot be controlled with endocrine therapies. Established breast cancer cell lines originally isolated from patient tumours provide an invaluable resource for studying mechanisms of cancer cell growth and for identifying approaches for killing cancer cells and for developing and testing new cancer drugs. We have used state-of-the-art CRISPR technology to engineer all the common ER mutations in breast cancer cell lines. These cell lines recapitulate the resistance to endocrine therapies that is observed in patients. By comparing gene expression profiles in ER mutant cells with those in endocrine therapy responsive, ER wild-type breast cancer cells, we have been able to identify a very small number of genes that are specifically activated in breast cancer cells that are making mutant ER. We have found that these mutant ER-specific genes are strongly predictive of poor likelihood of patient survival, evidencing their potential importance for endocrine therapy resistant breast cancer. The most prominent of these genes is itself a regulator of gene expression and has a well-known function in regulating cancer cell survival in other tumour types. We hypothesise that activation of this gene plays important roles in the enhanced survival and invasive properties of ER-mutant breast cancer. By using molecular approaches to manipulate the levels of this gene in ER wild-type and ER mutant breast cancer cells, either by over-expressing it or by "knocking-out" the gene, we can investigate the mechanisms by which this gene drives breast cancer cell survival, metastasis and to progress to identifying new treatment opportunities in this large group of very difficult to treat breast cancer patients.

乳腺癌是世界上最常见的癌症，每年导致女性四分之一的癌症诊断和六分之一的癌症死亡。女性荷尔蒙雌激素促进乳腺癌的发生及其进展。雌激素受体（ER）蛋白介导雌激素的细胞作用。雌激素与 ER 结合对于激活 ER 是必需的。激活的雌激素结合 ER 蛋白通过诱导共同驱动乳腺癌生长的基因表达来刺激乳腺癌的发展。大多数（>70%）乳腺癌是 ER 阳性，ER 阳性乳腺癌的标准治疗药物治疗通过阻断 ER 活性发挥作用。这些“内分泌疗法”已被证明是减少乳腺癌疾病和死亡的有效疗法。然而，许多患者会复发。内分泌治疗难治性转移性疾病不可避免地会出现复发率，即使在最初诊断并手术切除乳房肿瘤几十年后，复发率仍然保持不变，因此需要开发新的治疗方法。DNA测序的最新进展表明，ER基因发生了突变高达 40% 的肿瘤复发患者。这些突变的 ER 蛋白具有组成型活性，因此它们的活性不会被内分泌治疗所阻断。因此，ER 突变的乳腺癌患者无法通过内分泌治疗得到控制。最初从患者肿瘤中分离出来的已建立的乳腺癌细胞系为研究癌细胞生长机制、确定杀死癌细胞的方法以及开发和测试新的抗癌药物提供了宝贵的资源。我们使用最先进的 CRISPR 技术来设计乳腺癌细胞系中所有常见的 ER 突变。这些细胞系概括了在患者中观察到的对内分泌治疗的耐药性。通过将 ER 突变细胞中的基因表达谱与内分泌治疗敏感的 ER 野生型乳腺癌细胞中的基因表达谱进行比较，我们已经能够鉴定出极少数在产生突变 ER 的乳腺癌细胞中被特异性激活的基因。我们发现这些突变的 ER 特异性基因强烈预测患者生存的可能性较低，这证明了它们对内分泌治疗耐药的乳腺癌的潜在重要性。这些基因中最突出的基因本身就是基因表达的调节因子，并且在调节其他肿瘤类型中的癌细胞存活方面具有众所周知的功能。我们假设该基因的激活在增强 ER 突变乳腺癌的生存和侵袭特性方面发挥着重要作用。通过使用分子方法来操纵该基因在 ER 野生型和 ER 突变型乳腺癌细胞中的水平，无论是通过过度表达还是通过“敲除”该基因，我们可以研究该基因驱动乳腺癌的机制。癌细胞的存活、转移，并在这一大群非常难以治疗的乳腺癌患者中寻找新的治疗机会。