Escape from breast tumor dormancy: The convergence of obesity and menopause

Abstract

Obesity is associated with an increased risk of, and a poor prognosis for, postmenopausal (PM) breast cancer (BC). Our goal was to determine whether diet-induced obesity (DIO) promotes 1) shorter tumor latency, 2) an escape from tumor dormancy, and 3) an acceleration of tumor growth and to elucidate the underlying mechanism(s). We have developed in vitro assays and PM breast tumor models complemented by a noninvasive imaging system to detect vascular invasion of dormant tumors and have used them to determine whether obesity promotes the escape from breast tumor dormancy and tumor growth by facilitating the switch to the vascular phenotype (SVP) in PM BC. Obese mice had significantly higher tumor frequency, higher tumor volume, and lower overall survival compared with lean mice. We demonstrate that DIO exacerbates mammary gland hyperplasia and neoplasia, reduces tumor latency, and increases tumor frequency via an earlier acquisition of the SVP. DIO establishes a local and systemic proangiogenic and inflammatory environment via the up-regulation of lipocalin-2 (LCN2), vascular endothelial growth factor (VEGF), and basic fibroblast growth factor (bFGF) that may promote the escape from tumor dormancy and tumor progression. In addition, we show that targeting neovascularization via a multitargeted receptor tyrosine kinase inhibitor, sunitinib, can delay the acquisition of the SVP, thereby prolonging tumor latency, reducing tumor frequency, and increasing tumor-free survival, suggesting that targeting neovascularization may be a potential therapeutic strategy in obesity-associated PM BC progression. This study establishes the link between obesity and PM BC and, for the first time to our knowledge, bridges the dysfunctional neovascularization of obesity with the earliest stages of tumor development.

Dysregulation of miR-335-5p in People with Obesity and its Predictive Value for Metabolic Syndrome

“…The inhibition of Rap1 guards against obesity and metabolic disorders by governing food consumption and preserving leptin and insulin signaling [33]. Metabolic disorders associated with obesity can result in insulin resistance and amplified signaling via insulin and insulin-like growth factor receptors, which in turn activates downstream AKT and MAPK pathways while suppressing lipolysis [34].…”

WISER Survivor Trial: Combined Effect of Exercise and Weight Loss Interventions on Adiponectin and Leptin Levels in Breast Cancer Survivors with Overweight or Obesity

“…Leptin supports metastatic progression and tumor recurrence by increasing invasion and migration potential as well as stem-like characteristics in breast cancer cells [39]. In particular, an elevated leptin level due to dysfunctional adipose tissue may induce activation of dormant breast tumor cells [40]. Higher leptin levels are associated with an increased risk of breast cancer recurrence and worse overall survival in breast cancer patients [14].…”

Metabolic Profile and Negatively Association Between Insulin Resistance and Metastatic Incidence in Indonesian Primary Invasive Breast Cancer: A Cross-Sectional Study

“…Another study noted a significant correlation between cancer progression and obesity in postmenopausal women. 16 , 55 We used 60 years of age as the cut-off to define menopause per the NCCN guideline. Thus, this may contribute to the different findings of our study when compared with other published studies.…”

“…The pathogenesis basis of the convergence between menopausal status and obesity in advancing cancer progression lies in heightened neovascularization rate and earlier switching of the tumor to the vascular phenotype. 55 Genetics were also found to play a significant role in the interaction between insulin resistance and breast cancer in postmenopausal women. 56 The main limitation of this study is its cross-sectional design and the number of patients who met the subject selection criteria during this period was insufficient.…”