Macintyre, Benedict; (2021) Evaluating the role of glutamine-dependent metabolic pathways in MYC-induced mammary gland tumourigenesis. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

One of the major oncogenes dysregulated in breast cancer is MYC. MYC is a master regulator transcription factor that controls the expression of myriad genes involved in cell growth and metabolism. MYC transformation can render cells dependent on certain metabolic pathways, an important example of which is glutamine metabolism. Among MYC transcriptional targets are kidney-type glutaminase (GLS1), an enzyme regulating the first step of glutamine catabolism, and phosphoserine aminotransferase (PSAT1), an enzyme that utilises the amino group of glutamine for serine biosynthesis. Overexpression of MYC sensitises cells to glutamine deprivation and GLS1 inhibition. Hyperactivation of MYC is associated with increased GLS1 activity in basal-like and ER-negative breast tumours, and basal-like breast cancer cell lines are more sensitive to GLS1 inhibition. However, no direct relationship has been drawn between inhibiting GLS1, specific aminotransferase reactions downstream of GLS1, or both, and therapeutic effect in MYC-driven breast tumours. Herein we demonstrate that Gls1 deletion in the murine mammary gland delays MYC-induced tumour initiation, with tumours appearing histologically and metabolically distinct from controls. Consistently, Gls1KO tumours have decreased catabolism of glutamine carbon into the tricarboxylic acid cycle (TCA) cycle in comparison with control tumours. Nonetheless, Gls1KO tumours remain able to hydrolyse glutamine suggesting that compensatory mechanisms exist that permit MYC-induced tumour initiation and progression. We also find that deletion of Psat1 delays MYC-induced tumour initiation and progression. Psat1 deletion completely ablated serine biosynthesis in tumours and was sufficient to reduce total serine levels. Importantly, the effect of Psat1 deletion is enhanced by a serine- and glycine- deficient (-SG) diet. Psat1 deletion when combined with the -SG diet reduced glucose-derived carbon incorporation into nucleotides, while also decreasing total pools of nucleotides and one-carbon metabolites. The effects of either Gls1 deletion or perturbation of serine metabolism are markedly less pronounced in tumours induced by ERBB2, the murine ortholog of HER2, another oncogene commonly amplified in human breast cancers. These results reveal a clear functional connection between MYC overexpression and glutamine metabolism in mammary gland tumours in mice, providing further clinically relevant rationale for therapeutic targeting of components of glutamine metabolism in human MYC-high breast tumours.

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