The role of HOX genes in breast cancer dormancy and recurrence

在英国，每年有超过55000名女性被诊断出患有乳腺癌，每八名女性中就有一人在一生中患上了这种疾病。虽然乳腺癌的存活率相对较高，但转移是常见的现象，也是癌症患者的主要死亡原因。在转移过程中，恶性细胞离开原发肿瘤，在体内移动，到达次要的小生境，在那里它们可能进入休眠、缓慢循环的状态。这些播散的肿瘤细胞可以在几年甚至几十年内保持低数量，从而避开传统的化疗，然后重新激活并开始增殖，以定植于次要位置。由于缺乏适当的方法来研究休眠细胞，这种休眠和复发状态之间的转换大多被研究得很少。然而，人们认为，周围的肿瘤微环境在向这些休眠的细胞发出信号以唤醒它们方面发挥了作用。在这个开关中起作用的候选基因家族是HOX基因。这些基因编码转录因子，这些转录因子是胚胎发育的主要调节因子，有助于正确的身体模式。它们继续在成人组织中表达，以维持分化的细胞谱系，并确保动态平衡。这些基因中的大多数在大多数肿瘤类型中的表达都发生了变化，这表明这些关键基因的放松调控参与了癌症的发生。HOX基因的表达可以通过表观遗传学的改变来微调，从而导致对周围微环境的反应处于活跃或抑制状态，因此它们可能在癌症中从休眠状态到增殖细胞状态的转换中发挥作用。项目假设HOX基因参与了肿瘤的休眠和复发，与这些状态相关的HOX基因信号可能是乳腺癌的新的预后生物标志物和治疗靶点。在这个项目中，包括3D凝胶在内的休眠平台将被测试，以发现并比较两种状态下HOX基因的基因表达特征，以探索它们在疾病从休眠到复发过程中的作用。

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.