Targeting Tryptophan Catabolism: A Novel Method to Block Triple-Negative Breast Cancer Metastasis
Abstract
The vast majority of breast cancer deaths are the result of metastasis, due in part to the limited treatment options effective against metastatic disease. Thus, there is a great need for new therapeutics capable of preventing or inhibiting the formation and growth of metastases. This proposal addresses the overarching challenges of distinguishing aggressive breast cancers from more indolent tumors and identifying why some breast cancers become life-threatening metastases, with the goal of identifying new treatments to prevent or reduce metastatic spread and recurrence. Rationale: The process of metastasis involves multiple steps including migration and invasion of cells away from the primary tumor, survival in the bloodstream or lymphatics, colonization of the metastatic site, and outgrowth of the metastasis at distant sites. Normal breast epithelial cells are programmed to die when they become detached from their normal cellular environment, called a basement membrane. This detachment-induced cell death occurs in other types of epithelial cells as well; for instance, if physical damage scrapes off the epithelial cells that line the gut, they undergo cell death. Resistance to detachment-induced cell death (termed "anoikis," which is Greek for "homeless") is thought to be a critical to the survival of tumor cells that leave the primary tumor to travel through the vasculature or lymphatics to a distant metastatic site. In this proposal, we focus on a particular mechanism of anoikis resistance that we think could be targeted by novel therapeutics with the goal of preventing metastases. This is particularly important for the aggressive triple-negative subtype of breast cancer (TNBC) (so called because it lacks expression of estrogen and progesterone receptor and amplification of Her2) because it tends to metastasize at a higher rate and often within the first 5 years after diagnosis. Thus, this subtype of breast cancer has the worse prognosis, in part because it is often resistant to chemotherapy when it recurs and currently there is no effective targeted therapy for this subtype. Preliminary Studies: We previously found that TNBC cells can survive better in suspension than other breast cancer cell lines. To determine the mechanism(s) behind this, we analyzed gene expression of TNBC cells grown in forced suspension (to model detachment from the basement membrane) compared to cells grown in the attached condition. We made the novel discovery that several genes in the Kynurenine Pathway (KP) are upregulated by TNBC cells in suspension. The KP converts the essential amino acid tryptophan into a cellular energy source, and a product of this pathway is a substance called kynurenine (Kyn). Kyn binds to and activates a receptor (the Aryl Hydrocarbon Receptor [AhR]) that we also find to be increased in TNBC cells in suspension. Recently it was discovered that in brain cancer (glioma), kynurenine and AhR signaling lead to increased growth and migration of cancer cells. Interestingly, AhR is also expressed by immune cells, and kynurenine exerts an immune-suppressive effect, decreasing the ability of immune cells to recognize glioma cells. Importantly, the fact that TNBC is utilizing this pathway could not have been discerned from the existing large databases looking at primary tumors; however, our study uniquely revealed that TNBC upregulates this pathway in suspension. Our objective is to determine if this pathway explains the high metastatic potential of TNBC and perhaps it has an enhanced ability to avoid immune surveillance and destruction and thereby recurs earlier than other forms of the disease. We hypothesize that inhibition of the KP pathway, production of kynurenine or its binding to AhR will decrease TNBC cell survival in suspension and decrease the metastatic ability of TNBC tumors. The following specific aims will test our hypothesis: Aim 1: Determine if inhibition of TDO affects TNBC cell invasio
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510039
Entities
People
- Jennifer K Richer
Organizations
- United States Army
- University of Colorado Denver