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Abstract

Breast cancer tumors are recognized to be highly heterogeneous, and differences in their metabolic phenotypes are less well understood. While a number of mostly RNA-based profiling approaches have been developed aiming to improve diagnostic and therapy decision, few have entered clinical practice. Alongside metabolic alterations, tumor hypoxia has consistently been associated with a more aggressive malignant phenotype. Both tumor hypoxia and dysregulated metabolism are classical features of cancer and currently no studies either systematically examine the prognostic value of metabolism associated enzymes in a large cohort of breast cancer patients or their alterations in oxygen deprived conditions. For my PhD project, I undertook systematic profiling of metabolic enzymes in a cohort of 801 breast cancer patients to evaluate the relationship between profiles of metabolism-associated protein expression and clinicopathological characteristics. I identified three metabolic clusters of breast cancer that are significantly correlated with overall and recurrence-free survival, but do not reflect the common receptor-defined subtypes. Furthermore, high protein expression of the Serine Hydroxymethyltransferase 2 (SHMT2) and the Amino Acid Transporter (ASCT2), were identified as independent prognostic factors for overall and recurrence-free survival in breast cancer patients. Another aspect of research revealed the heterogeneous regulation of metabolic enzymes during oxygen deprived conditions and elucidated glutamate-ammonia ligase(GLUL) as a novel effector of the hypoxic response in breast cancer cell lines. The findings of my thesis are the first to demonstrate metabolic heterogeneity at the protein level in a large breast cancer cohort and highlight the clinical significance of SHMT2 and ASCT2 protein expression as new independent prognostic markers in breast cancer patients. Additionally, GLUL protein expression was identified as a novel effector of the hypoxic rewiring process in breast cancer cell lines. These findings may pave the way for the utilization of SHMT2 and ASCT2 as potential targets for innovative personalized therapy and advance the understanding of metabolic adaptation during hypoxic conditions.