Endocrine Abstracts

Introduction: Although breast cancer (BC) is considered a treatable disease, >30% of patients with hormone receptor positive tumours will suffer recurrence post endocrine therapy. One of the fundamental features of cancer cells is their ability to modulate cell metabolism to facilitate survival, stress response, and proliferation. Increasing evidence suggests that these mechanisms play key roles in the development of treatment resistance. Recent publications from our group have shown that an androgenic steroid environment is associated with poor response to aromatase inhibitor (AI) therapy. Of significance, we have previously shown that androgens mediate increased expression of serum-and-glucocorticoid kinase-3 (SGK3), a known substitute for AKT, that is associated with second-line resistance in BC. Here we investigate the role of androgens in modulating cellular metabolism in BC cell lines via SGK3 regulated mechanisms.

Methodology: Using in-house isogenic models of endocrine resistance (MCF7 and LetR) and a novel SGK3-PROTAC1 degrader, we explore the impact of androgenic steroids and SGK3 inhibition on intracellular lipid accumulation and cell metabolism using a combination of Seahorse Mito Stress assays, flow cytometry, protein analysis and imaging studies.

Results: SGK3 inhibition associates with the stabilisation of 17βHSD4, a D-bifunctional enzyme that plays a key role in peroxisomal lipid β-oxidation and androgenic steroid inactivation. Exposure of BC cells to androgens influenced mitochondrial morphology, coincidental with increased mitochondrial membrane potential, mitochondrial mass and glycolytic capacity. Additionally, androgen exposure altered intracellular lipid accumulation and distribution.

Conclusions: Regulation of 17βHSD4 highlights the potential role of androgen driven SGK3 in modifying the steroidogenic tumour environment. This altered steroid microenvironment mediates significant changes in cell metabolism, which mirrors disorders of androgen excess in women, such as PCOS, which are linked to lipid toxicity and deranged metabolism. Further studies will explore androgen mediated SGK3 in regulating steroid homeostasis and associated metabolic reprogramming as drivers of endocrine resistance.