DESCRIPTION (provided by applicant): Breast cancer is the most prevalent cancer type (~1,383,500 new cases/year), the leading cause of cancer-associated death among woman worldwide (~458,400 death/year), and the 2nd most lethal cancer in the United States. Obesity happens in 36% adults in the United States, contributing to breast-cancer incidence and progression. Whereas several inflammatory cytokines are implicated in breast cancer, their distinct roles in obesity-driven cancer progression are largely elusive. Our preliminary data identified interleukin-1 (IL-1)/IL-1R1 signaling cascade to be required for obesity-driven breast cancer progression (ODBP) from different tumor models. Our long-term goal is to understand the mechanisms that underlie ODBP, and to prevent or treat obese breast-cancer patients. The objective of the proposed research is to determine the mechanism how NLRC4-inflammasome and IL-l/IL-1R1 axis drive breast-cancer progression under obese condition. Our central hypothesis is that some danger signal from obese tumors induces NLRC4-inflammasome activation and subsequent IL-1β production in tumor-associated stroma, which in turn promotes tumor progression through the induction of angiogenesis. We thus propose the following specific aims: Specific Aim 1: Determine the relevance of NLRC4-inflammasome in ODBP. Specific Aim 2: Determine how NLRC4 promotes ODBP within the tumor microenvironment; Specific Aim 3: Explore novel combinatory regimens to treat obese breast-cancer patients. Our results are expected to have a positive impact on guiding targeted therapy for inhibiting the breast-cancer progression in obese patients. The potential application of available agents, such as anakinra (known to be safe and effective for the treatment of other diseases) or some long-lasting Casp-1 inhibitors for breast-cancer therapy, would significantly shorten the drug development process. The study may potentially benefit the over one third of breast-cancer patients considering that ~36% adults are obese in the United States.