Systematic Characterization of Olfactory Receptor Expression and Function in Breast Cancer
Abstract
Cancer stinks -- literally! Using their sense of cell, fruit flies, mice, and dogs are all able to detect the presence of cancer in breath, blood, and urine samples collected from cancer patients. As cancer cells grow, they are generating small, gaseous, carbon-based by-products that our brains recognized as odorants. Humans, and other mammals, rely on our sense of smell to survey our surroundings, such as what is cooking on the stove or the burning of a log in the fireplace. Our sense of smell depends on the interaction between these small volatile organic compounds (VOCs) and proteins found on the surface of olfactory sensory neurons, known as receptors, within in our noses, leading to the stimulation of neurons in the brain that consciously identify the smell. Most individuals are aware that exposure to common sources of pollution, such as automotive exhaust fumes, can increase an individual s cancer risks and typically associate these as bad smells. On the other hand, floral smells are pleasant and have been incorporated into many lotions and perfumes men and women use on a regular basis. However, we know little about how perfumes and other pleasant-smelling environmental stimuli may affect breast cancer progression. Emerging evidence suggests that odors produced by the cancer cells themselves may influence the course of the disease. Both cancer cells and immune macrophages have been shown to express olfactory receptors (ORs) on their surfaces, suggesting that cancer cells may be able to "smell" themselves. This has surprised the cancer research community as the expression of these receptors is thought to be restricted to the nasal cavity. Several studies have suggested that the binding of odorants to the surface of the cancer cells actually leads to increased prostate cancer cell migration and increased metastatic lung lesions in mice. In addition, immune macrophages that play a pro-tumorigenic role in breast cancer have also been shown to have increased migration and recruitment to tumors as a result of OR overexpression. The studies proposed in this grant will characterize how both macrophages and tumor cells use ORs and odorants to affect disease outcome. The objective of this proposal is to provide data on the molecular consequences of odorant production by breast cancer cells and determine whether OR activation in both tumor cells themselves and infiltrating immune cells leads to a tumor microenvironment that is more prone to metastases and an overall poorer prognosis in breast cancer patients. The studies outlined in this proposal, while basic in nature, will truly advance our understanding of some molecular drivers of aggressive breast cancer. We aim to gain a better understanding of the types of ORs that are expressed on immune cells infiltrating the tumor and tumor cells themselves. We will also generate data identifying the types of odorants that stimulate these receptors and the cellular consequences of this stimulation leading to aggressive disease phenotypes. Additionally, we will determine whether environmental odorant exposure alters the course of disease. OR signaling in cancer is an emerging area of research. As a result, we will be among the first to explore the role of OR expression and function in breast cancer and will truly meet the goals of the Breast Cancer Research Program mission and Level 1 Breakthrough funding to identify novel avenues of investigation. We believe that the data we generate can have an immediate impact on breast cancer patients; our studies will provide data informing patients (and their physicians) on whether they should be concerned about the odors they may be exposed to before and after diagnosis. By exposing a mouse model of breast cancer to environmental odorants and assaying disease progression, we will determine whether certain odors can contribute to the aggressiveness of the disease and identify why some breast cancers become life-threatening
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 29, 2016
- Source ID
- W81XWH1510438
Entities
People
- Kellye Kirkbride
Organizations
- United States Army
- Vanderbilt University