Baenke, F; (2013) Metabolic dependencies of breast cancer cells. Doctoral thesis , UCL (University College London).

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Abstract

Cellular metabolism is one of the core processes for cell growth and proliferation. This process is altered in cancer cells as most solid tumours exhibit increased glucose uptake and lactate secretion, a feature known as the Warburg effect. These metabolic changes are the consequence of oncogene activation, loss of tumour suppressor function and/or mutations in metabolic enzymes. However, cancer cell metabolism is not limited to the Warburg effect and the exact role the metabolic machinery plays in facilitating proliferation and cell survival in different cancer types is still poorly understood and requires further study. Breast cancer is a complex and heterogeneous disease at the molecular level. In addition, the PI3K/AKT signalling pathway is frequently activated in breast cancers due to loss of the PTEN tumour suppressor, oncogenic activation of PIK3CA or overexpression of certain growth factor receptors. This study aimed to investigate whether the metabolic requirements of breast cancer cell lines are determined by their molecular alterations. By using RNA interference (siRNA), the expression of 231 metabolic enzymes, transporters and metabolic regulators of the cellular glucose and lipid metabolism were ablated in a panel of 14 breast cancer cell lines and 3 non-malignant breast cell lines with distinct molecular characteristics. Solid breast tumours are known to have regions of high/low delivery of nutrients and oxygen that facilitate changes in the metabolic dependencies of cancer cells that reside within these areas. Moreover, these solid tumours that contain regions of poor oxygen delivery are associated with cancers refractive to treatment and that have poorer overall survival. Thus, to examine the metabolic dependencies of cells that reside in these regions, an environment of low oxygen was recapitulated and the effect of silencing of metabolic genes on cell survival was assessed. Crucially, this approach has led to the identification of previously known and novel metabolic genes that are essential for survival of breast cancer cells for each of the defined breast cancer subgroups. In addition, the characterisation of the metabolic requirements and processes revealed that each subgroup displays a distinct metabolic phenotype that might provide potential novel molecular targets that could be exploited therapeutically.

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