The role of HOX genes in breast cancer dormancy and recurrence

HOX基因在乳腺癌休眠和复发中的作用

• 批准号: 1945073
• 金额: --
• 依托单位: University of Nottingham
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-1945073
• 关键词: role; HOX; genes; breast; cancer

Each year over 55,000 women are diagnosed with breast cancer in the UK, with one in eight women developing the disease in their lifetime. Although the survival rate for breast cancer is relatively high, metastasis is a common occurrence and is the primary cause of death in cancer patients. In metastasis, malignant cells leave the primary tumour, move through the body and reach a secondary niche where they may enter a dormant, slow-cycling state. These disseminated tumour cells can remain at low numbers for years or even decades, evading traditional chemotherapies, before reactivating and beginning proliferation to colonise the secondary location.The switch between this dormant and recurrent state is mostly understudied due to the lack of suitable methods for studying dormant cells. However it is thought that the surrounding tumour microenvironment plays a role in signalling these dormant cells to reawaken. A candidate family of genes that act within this switch are the HOX genes. These genes encode transcription factors that are master regulators of embryogenesis, instrumental in correct body patterning. They continue to be expressed in adult tissues to maintain differentiated cell lineages and ensure homeostasis. Most of these genes have shown altered expression across most tumour types, suggesting that the deregulation of these critical genes are involved in carcinogenesis. HOX gene expression can be fine-tuned via epigenetic changes to result in an active or repressed state in response to the surrounding microenvironment, and thus it is possible that they would play a role in the switch between dormant and proliferative cell states in cancer.The project hypothesis is that HOX genes are involved in tumour dormancy and relapse and that HOX gene signatures related to these states could represent novel prognostic biomarkers and therapeutic targets for breast cancer. In this project, platforms of dormancy, including 3D gels which physically confine cells to induce a dormant-like state, will be tested to discover and compare the gene expression signatures of HOX genes between the two states, in order to explore their role in disease progression from dormancy to relapse.

在英国，每年有超过55，000名女性被诊断患有乳腺癌，其中八分之一的女性在其一生中患上这种疾病。虽然乳腺癌的存活率相对较高，但转移是常见的，并且是癌症患者死亡的主要原因。在转移中，恶性细胞离开原发肿瘤，穿过身体并到达次级龛，在那里它们可能进入休眠，缓慢循环状态。这些扩散的肿瘤细胞可以在数年甚至数十年内保持低数量，逃避传统的化疗，然后重新激活并开始增殖以定植第二位置。由于缺乏研究休眠细胞的合适方法，这种休眠和复发状态之间的转换大多未得到充分研究。然而，人们认为周围的肿瘤微环境在向这些休眠细胞发出信号以重新唤醒中起作用。在该开关内起作用的候选基因家族是HOX基因。这些基因编码的转录因子是胚胎发生的主要调节因子，有助于正确的身体模式。它们继续在成体组织中表达，以维持分化的细胞谱系并确保稳态。这些基因中的大多数在大多数肿瘤类型中表现出表达改变，这表明这些关键基因的失调与致癌作用有关。HOX基因表达可以通过表观遗传变化进行微调，以响应周围微环境而产生活性或抑制状态，该项目假设HOX基因参与肿瘤休眠和复发，与这些状态相关的HOX基因特征可能代表新的预后生物标志物和乳腺癌的治疗靶点。在这个项目中，休眠的平台，包括物理限制细胞以诱导休眠样状态的3D凝胶，将被测试以发现和比较两种状态之间HOX基因的基因表达特征，以探索它们在疾病从休眠到复发的进展中的作用。