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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
7R01CA200673-04
Application #
9838489
Study Section
Tumor Microenvironment Study Section (TME)
Program Officer
Sathyamoorthy, Neeraja
Project Start
2015-12-07
Project End
2020-11-30
Budget Start
2019-02-22
Budget End
2019-11-30
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Florida
Department
Pathology
Type
Schools of Medicine
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
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