Triple Negative Breast Cancer: Tryptophan Degradation Pathway Promotes Metastatic Phenotypes

Thomas Rogers PhD Candidate- Cancer Biology Graduate Program Laboratory of Jennifer Richer Department of Pathology University of Colorado-Anschutz Medical Campus Laboratory of CU Cancer Center investigator, Jennifer Richer, PhD.MedicalResearch.com Interview with:
Thomas Rogers
PhD Candidate- Cancer Biology Graduate Program
Laboratory of Jennifer Richer
Department of Pathology
University of Colorado-Anschutz Medical Campus
Laboratory of CU Cancer Center investigator, Jennifer Richer, PhD.

Medical Research: What is the background for this study? What are the main findings?

Response:

Background: Survival while detached from a basement membrane is a critical trait of cancer cells progressing through the metastatic cascade. This is particularly important for the triple-negative breast cancer (TNBC) subtype, which lacks estrogen and progesterone receptors and does not have amplification of HER2, and has a peak risk of recurrence within the first three years post-diagnosis. Triple-negative breast cancer also has the highest mortality rate in the first five years as compared to other breast cancer subtypes. We performed global profiling of TNBC cells in adherent versus forced suspension culture conditions after24 hours. These data revealed that triple-negative breast cancer cells surviving in suspension upregulate multiple genes involved in tryptophan catabolism, also known as the kynurenine pathway, including the rate limiting enzyme tryptophan 2,3,-dioxygenase (TDO2) and kynureninase (KYNU). Kynurenine, a key intermediate metabolite of this pathway activates the aryl hydrocarbon receptor (AhR), which was also up-regulated in TNBC cells grown in forced-suspension culture.

Main Findings: Critical enzymes of the kynurenine pathway, TDO2 and KYNU, are upregulated in triple-negative breast cancer cells grown in forced-suspension culture. Furthermore, secreted kynurenine doubles in TNBC cells in forced-suspension culture as measured by high performance liquid chromatography (HPLC). Kynurenine activates the aryl hydrocarbon receptor in triple-negative breast cancer cells grown in forced-suspension culture. Targeting TDO2 and AhR with small molecule inhibitors or short hairpin RNAs decreased survival in suspension, migration/invasion, and proliferation of TNBC cells. Lastly, TDO2 gene expression is higher in invasive ductal breast carcinoma as compared to normal breast tissue and is significantly higher in estrogen receptor negative tumors as compared to estrogen receptor positive tumors. In addition, patients with higher (above-median) TDO2 expression in their primary tumor had significantly shorter overall survival than those with low TDO2.

Conclusions: The kynurenine pathway is activated in TNBC cells in forced suspension and facilitates the invasive/metastatic phenotype of this aggressive breast cancer subtype. Our findings support further investigations into targeting the enzyme TDO2 in TNBC as a novel therapeutic strategy with potential to reduce TNBC mortality rates. Kynurenine is well-known to suppress immune cell function via activation of AhR.

Medical Research: What should clinicians and patients take away from your report?

Response: The tryptophan catabolism or kynurenine pathway, initiated by either indoleamine 2,3-dioxygenase (IDO1) or TDO2, has been implicated in cancer biology with many studies focused on IDO1 as the rate limiting enzyme, not TDO2. Currently there are a number of clinical trials focused on targeting IDO1 using Indoximod (1-methyl-tryptophan) in hopes of relieving immune suppression and boosting anti-tumor immune response in combination with standard of care chemotherapy. Importantly, 1-methyl-tryptophan does not target TDO2. Our studies suggest that targeting TDO2 as well as IDO1 may be beneficial to triple-negative breast cancer patients, who currently do not have any tumor specific targeted therapy.

Tryptophan degradation is a necessary process that occurs naturally in the body. Tryptophan is an essential amino acid found in our everyday diets. This study is NOT suggesting that consuming more tryptophan will cause breast cancer. This study IS suggesting that the tryptophan catabolism pathway is revved-up in certain cancer cells, resulting in an increased amount of kynurenine. Screening/targeting of this pathway with drugs that target TDO2 and reduce synthesis of kynurenine may be a new therapeutic strategy for TNBC.

Medical Research: What recommendations do you have for future research as a result of this study?

Response: Future studies will elucidate the role of the kynurenine pathway in pre-clinical models of TNBC in immune competent mice. In this manner we can study both the autocrine effects of this pathway on tumor cells and paracrine effects on the immune system that may enable TNBC to evade immune recognition and destruction.

Citation:

Abstract presented at 2014 San Antonio Breast Cancer Symposium
Pathway that degrades holiday turkey fuels metastasis of triple negative breast cancer
University of Colorado Cancer Center.