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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. [ABSTRACT FROM AUTHOR]