Senescent obesity signature in breast cancer: a paradigm of reverse cardio-oncology

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Abstract
The field of reverse cardio-oncology examines how subclinical and overt cardiometabolic dysfunction—such as obesity—fuels breast cancer (BCa) risk and altered tumour biology through shared mechanisms such as chronic inflammation, hormonal dysregulation, and cellular senescence. Limitations of body mass index (BMI) have prompted the development of refined obesity phenotypes, including metabolically healthy vs unhealthy obesity and sarcopenic obesity that more accurately stratify BCa risk. Reverse cardio-oncology is conceptually distinguished from traditional cardio-oncology by focusing on how cardiometabolic impairment—even in the absence of manifest cardiovascular disease—increases BCa incidence and worsens prognosis. Within a common-soil framework, senescent adipose tissue is recognized as a key driver of breast tumour microenvironment remodelling through senescence-associated secretory phenotype (SASP), epigenetic reprogramming, and immunosenescence. Emerging translational strategies—including lifestyle modification, cardiometabolic therapies such as GLP-1 receptor agonists and SGLT2 inhibitors, and senolytic approaches—highlight opportunities to integrate cardiovascular and oncologic prevention and treatment in women with or at risk for BCa. Overall, this review synthesizes current knowledge on obesity’s mechanistic links to BCa within a reverse cardio-oncology paradigm and provides a conceptual foundation for improved risk stratification and interdisciplinary clinical management.
Funding Information
  • Ministero dell'Università e della Ricerca
  • National Recovery and Resilience Plan

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