Still, ER; (2018) The requirement and regulation of the glutamine transporter, ASCT2 in mammary gland tumorigenesis. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

In order to survive and proliferate within the challenging tumour microenvironment, cancer cells adapt their metabolism to meet their increased energetic and biosynthetic requirements, whilst also maintaining the redox balance. These changes in metabolism are dependent on both the genetic alterations driving tumorigenesis and the tissue of tumour origin. The first aim of this project was to determine whether metabolic changes in mammary gland tumours are determined by the initiating genetic event. To do this, this project compared the metabolic remodelling associated with the transformation of the mammary gland by two major oncogenes involved in breast cancer, MYC and ErbB2. This analysis revealed metabolic differences between both tumours and the normal mammary gland and between the two tumour types. Having confirmed that metabolic changes in tumours are determined by the initiating genetic event, this project then wanted to determine whether these metabolic differences could be exploited to develop new therapeutic strategies against either type of tumour. One of the major differences observed between these two tumour types was the increased glutamine catabolism in MYC-induced tumours compared to ErbB2 induced tumours. This was associated with the increased expression and N-glycosylation of the glutamine transporter, ASCT2. The regulation of ASCT2 by MYC in MYC-induced tumour cells was confirmed. Knockdown of ASCT2 revealed that the transporter is required for the proliferation and survival of cells isolated from MYC-induced tumours. This suggests that ASCT2 may be a good therapeutic target against tumours with high MYC activity. Previous work has demonstrated the difficulties in directly targeting ASCT2, due to its similarity with other amino-acid transporters. By understanding more about how ASCT2 is regulated, it is believed that more specific therapeutic strategies could be developed that indirectly target ASCT2 through one of its regulatory pathways. Thus, this study also investigated the link between the hexosamine biosynthesis pathway (HBP), glycosylation and glutamine metabolism, demonstrating that glutamine is required for the N-glycosylation of ASCT2. This confirmed that ASCT2 stability is regulated by glutamine, suggesting that glutamine availability may alter the transporter’s activity.

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