In a groundbreaking development that may transform therapeutic strategies for hormone receptor-positive (HR⁺) breast cancer, new research reveals that fasting significantly enhances the efficacy of endocrine therapy through the activation of glucocorticoid receptor (GR) signaling. This discovery illuminates a novel intersection between metabolic regulation and cancer therapy, proposing glucocorticoid agonists as potent mimetics of fasting’s beneficial anti-tumor effects, thereby opening promising avenues for clinical intervention.
Fasting and fasting-mimicking diets (FMDs) have garnered attention within oncological research for their potential to induce robust anti-tumor responses by orchestrating multiple biological pathways simultaneously. However, the clinical application of such dietary restrictions remains encumbered by concerns around malnutrition and patient quality of life. Addressing this challenge, the latest study identifies glucocorticoid receptor agonists, such as dexamethasone (Dexa), as pharmacological agents capable of replicating key molecular changes induced by fasting and thereby amplifying the impact of standard endocrine treatments.
At the metabolic interface, fasting induces a cascade of physiological adjustments — most notably reduced serum glucose and insulin levels — which culminate in the dampening of the AKT–mTOR signaling axis, a pathway intimately involved in cancer cell proliferation and survival. The research demonstrates that these metabolic shifts are intricately linked to the activation of GR signaling, establishing this mechanism as a central mediator of fasting’s potentiation of endocrine therapy in breast cancer. The glucocorticoid receptor thus emerges as a pivotal node connecting metabolic state to tumor suppression.
Steroid hormone receptors (SHRs) including the androgen receptor (AR) and progesterone receptor (PR), alongside estrogen receptor alpha (ERα), exhibit extensive genomic overlap, orchestrating tumor-suppressive transcriptional programs in HR⁺ breast cancer. The study elucidates how fasting elevates circulating cortisol and progesterone, thereby selectively augmenting GR and PR activity. This receptor crosstalk enhances the responsiveness of breast tumors to endocrine agents, suggesting that the hormonal milieu shaped by fasting creates a more favorable environment for therapeutic efficacy.
The dichotomous role of progesterone signaling is underscored by clinical trials investigating PR modulation with conflicting outcomes. While PR agonists in combination with letrozole are under evaluation, inhibition of PR via mifepristone paradoxically also decreases tumor proliferation in certain contexts. This paradox is partly attributed to mifepristone’s dual action as a PR antagonist and a dose-dependent GR agonist, highlighting the complexity of steroid receptor pharmacodynamics and the nuanced balance required to optimize treatment responses.
Historical clinical trials from decades past reported only modest improvements when glucocorticoids were added to endocrine regimens in breast cancer therapy. These limited benefits are now reconsidered under the lens of receptor subtype specificity; earlier studies did not stratify patients by receptor status, inadvertently including triple-negative breast cancer patients for whom GR activation can promote tumor growth and metastasis. The current research clarifies that GR agonism exerts its most profound antiproliferative effects specifically within the luminal A subset of HR⁺ breast cancers, which possess a distinct receptor expression profile.
Preclinical in vivo studies further reinforce the therapeutic promise of glucocorticoid receptor activation. In immunocompetent mouse models, co-administration of dexamethasone with tamoxifen significantly retarded tumor growth and extended survival compared to tamoxifen alone. Immune profiling revealed an immunological equilibrium without overt suppression or activation, with a notable reduction in PD-L1 expression on certain immune populations. Given that low PD-L1 is associated with heightened anti-cancer immune activity, this suggests that dexamethasone may exert complementary systemic effects that enhance tumor control beyond direct tumor cell modulation.
While chronic corticosteroid use is traditionally linked to adverse outcomes such as immunosuppression, bone density loss, and endocrine disruption, the observed balanced immune state in these models invites reconsideration of glucocorticoid administration in a carefully calibrated therapeutic context. The results argue for a reevaluation of glucocorticoid drugs’ safety profile in cancer therapy, especially when combined with tailored endocrine agents and possibly implemented in fasting mimetic regimens.
From a molecular standpoint, glucocorticoid receptor activation drives a gene expression program that reinforces luminal differentiation and suppresses proliferative cues. This shift towards a more differentiated tumor phenotype correlates strongly with improved prognosis and decreased cellular proliferation, anchoring the GR’s role as a tumor suppressor in HR⁺ breast cancer biology. The ability to pharmacologically mimic fasting-induced GR activation with existing and clinically approved drugs streamlines the translational path for these findings.
The prospect of replacing stringent dietary regimens with pharmaceutical glucocorticoid receptor agonists holds substantial clinical appeal, potentially circumventing the nutritional and lifestyle challenges of fasting. This approach could democratize the metabolic benefits observed in preclinical and early clinical scenarios, making them accessible and scalable across patient populations.
Looking forward, this study lays a foundation for future clinical trial designs that integrate glucocorticoid receptor agonists as adjuncts to endocrine therapy specifically for HR⁺ breast cancer. Such trials will need to meticulously stratify patients by receptor status and monitor immune parameters to optimize dosing schedules and minimize adverse effects.
In summary, the elucidation of glucocorticoid receptor signaling as a central mediator of the fasting-enhanced response to endocrine therapy not only redefines the biological underpinnings of metabolic interventions in breast cancer management but also introduces a compelling pharmacological strategy. By co-opting established glucocorticoid drugs, clinicians may soon have at their disposal a powerful tool to amplify the efficacy of hormone-based cancer treatments, improving patient outcomes while reducing the burden of dietary restrictions.
Subject of Research:
The interplay between fasting-induced metabolic changes and hormone receptor signaling in enhancing endocrine therapy efficacy in hormone receptor-positive breast cancer, focusing on glucocorticoid receptor activation.
Article Title:
Fasting boosts breast cancer therapy efficacy via glucocorticoid activation.
Article References:
Padrão, N., Severson, T.M., Gregoricchio, S. et al. Fasting boosts breast cancer therapy efficacy via glucocorticoid activation. Nature (2025). https://doi.org/10.1038/s41586-025-09869-0
Image Credits:
AI Generated
DOI:
https://doi.org/10.1038/s41586-025-09869-0
Keywords:
Fasting, hormone receptor-positive breast cancer, glucocorticoid receptor, dexamethasone, endocrine therapy, progesterone receptor, steroid hormone receptors, metabolic regulation, AKT–mTOR signaling, PD-L1, tumor proliferation, immune modulation
