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-1? 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.
The proposed research aims to establish NLRC4 inflammasome activation as the major mechanism that underlies obesity-driven breast cancer progression. Interleukin-1? is activated upon NLRC4 activation within myeloid cells to promote tumor-associated angiogenesis. Targeting NLRC4/interleukin-1? thus represents a novel treatment to obese breast cancer patients, in conjunction with current standard therapy to breast cancer.
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