The role of HOX genes in breast cancer dormancy and recurrence

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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.