Evaluating the impact of the steroid milieu on cancer cell metabolism in endocrine resistant breast cancer
Dr M McIlroy
Dr T Chonghaile
Monday, December 02, 2019
Competition Funded PhD Project (Students Worldwide)
There is strong epidemiological and historical evidence which suggests that estrogens may not be the sole steroid drivers of breast cancer. Understanding individual inter-tumour steroidogenesis will be critical to evaluating this clinically as it is known that elevated levels of weak androgens are associated with breast cancer risk >2 years prior to cancer detection. We hypothesise that abundant androgenic steroid precursors, such as androstenedione (4AD), promote a metabolically deviant, endocrine resistant breast cancer phenotype. This study therefore sets out to address the impact of the global steroid milieu and its relevance to breast tumour biology, the impact on cell metabolism and response to treatment.
Aims: Using well established models of aromatase inhibitor resistance we will determine the fate of the steroid precursor androstenedione (4AD) in vitro, and pair this with quantification data on the steroidogenic enzymes present. This will be extrapolated to tumour samples from patients that responded to AI therapy in comparison to those who did not. We will culture primary tumour associated adipocytes in 4AD and then evaluate how it is metabolised. This conditioned medium will be applied to our models of resistance and we can evaluate its impact on cell metabolism, autophagy and stemness.
Techniques and Methodology: Using cell models of AI resistance we can explore the impact of tumour derived steroids on cell metabolism, stemness and autophagy. We can interrogate well annotated clinical specimens to build a comprehensive picture of the steroid milieu in AI resistant and sensitive tumours using highly sensitive LC MS/MS and iTRAQ to evaluate steroidogenic enzymes. Finally, using our models of resistance we can evaluate the potential impact of drugs targeting cell metabolism, such as the novel
ATPase inhibitor (HY-111651), either as a solo agent or in combination with Metformin.
Impact on breast cancer research: Steroid levels are known to be altered by diet, exercise and other lifestyle choices; understanding their potential role in breast cancer development could therefore have wideranging effects. This research area has the potential to be extrapolated into a large-scale global study that may have a radical impact on our understanding of breast cancer development. The proposed study will reexamine breast tumour biology through a fresh lens and provide information on the impact of the altered steroid environment on cancer cell metabolism.