INS and cancer: The local and systemic alterations may directly affect cancer cells via activation of signaling pathways (e.g., estrogen, insulin/IGF, Janus-activated kinase/signal transducer and activator of transcription factor, etc.)or alterations in cellular metabolism or can indirectly affect the tumor microenvironment to promote cell proliferation, angiogenesis, and invasion.26–28 In addition, obese women have had greater tumor proliferation in several studies.21,29,30 Such data do not establish that BMI contributes to adverse tumor characteristics directly.