SGK3 and lipid remodelling: a key player in androgen-mediated metabolic dysregulation in endocrine-resistant breast cancer

Stephanie Agbana; Rachel Bleech; Tanya Schloms; Dario Alessi; Michael W. O; Marie McIlroy

doi:10.1530/endoabs.117.OP4.2

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Endocrine Abstracts (2026) 117 OP4.2 | DOI: 10.1530/endoabs.117.OP4.2

SFEBES2026 Oral Poster Presentations Endocrine Cancer and Late Effects (4 abstracts)

SGK3 and lipid remodelling: a key player in androgen-mediated metabolic dysregulation in endocrine-resistant breast cancer

Stephanie Agbana ^1,2 , Rachel Bleech ^1,2 , Tanya Schloms ^1,2 , Dario Alessi ³ , Michael W. O’Reilly ^1,4 & Marie McIlroy ^1,2

Author affiliations

¹Androgens in Health and Disease Research Group, Department of Surgery, Royal College of Surgeons in Ireland (RCSI), Dublin, Ireland; ²Endocrine Oncology Research Group, Department of Surgery, Royal College of Surgeons in Ireland (RCSI), Dublin, Ireland; ³MRC Protein Phosphorylation and Ubiquitylation Units, University of Dundee, Dundee, United Kingdom; ⁴Department of Endocrinology, University of Medicine and Health Sciences, RCSI, Dublin, Ireland

Introduction: Cancer cells often undergo significant metabolic reprogramming to meet the demands of rapid growth, adaptation to stress, evasion of cell death, and the development of therapeutic resistance. Our group previously demonstrated that an androgenic steroid environment arising post-aromatase inhibitor (AI) therapy correlates with unsustained response to therapy in breast cancer (BC). Notably, androgens upregulate serum-and-glucocorticoid-regulated kinase 3 (SGK3), a recognised functional substitute for AKT that is implicated in second-line treatment resistance. Here, we investigate the role of SGK3 in regulating lipid metabolism in BC cells under androgenic conditions and the impact on cell survival

Methodology: Using in-house isogenic models of endocrine-resistant breast cancer (MCF7/MCF7-Aro-LetR and ZR75.1/ZR75.1-Aro-LetR) and a novel SGK3 protein degrader (SGK3-PROTAC1), we assessed the effects of SGK3 degradation on lipid accumulation and metabolism through Seahorse Mito Stress assays, lipidomic assays, flow cytometry, protein analysis, and fluorescence imaging under androgenic conditions.

Results: AI-resistant cells exhibited enhanced metabolic plasticity, reflected by increases in mitochondrial mass, membrane potential, respiratory activity, and glycolytic capacity. These cells also displayed significantly higher fatty acid uptake and lipid droplet accumulation. Notably, SGK3 degradation disrupted both lipid accumulation and intracellular lipid distribution. This metabolic perturbation sensitised AI-resistant cells to ferroptosis, a lipid-dependent form of cell death, which was rescued by ferroptosis inhibitors. Furthermore, SGK3 loss stabilised 17βHSD4, a key enzyme involved in peroxisomal β-oxidation and androgen inactivation, underscoring a critical link between SGK3, lipid metabolism, and ferroptotic vulnerability.

Conclusions: An androgenic steroid microenvironment induces marked metabolic reprogramming in BC cells, reminiscent of metabolic dysregulation observed in disorders of androgen excess such as PCOS. SGK3 emerges as a critical regulator linking androgen signalling, lipid metabolism, and ferroptosis sensitivity. Targeting this pathway may offer new therapeutic avenues to overcome endocrine resistance in breast cancer.