Olga Novikov Wins Dean’s Award at Graduate Research Symposium.
Olga Novikov, a MD/PhD candidate researching possible environmental factors of breast cancer, was named winner of the School of Public Health Dean’s Award at the 2015 Graduate Research Symposium.
Novikov’s winning entry was titled “The Role of Endogenous and Environmental AHR Ligands in Mammary Epithelial Cell Tumor Growth and Invasion.” Novikov said her research is centered on aryl hydrocarbon receptor (AHR), a protein implicated as a possible trigger of breast cancer after binding with certain environmental pollutants.
“We found that products of metabolism of an essential amino acid—tryptophan—can drive AHR activity, so that if tryptophan metabolism is abnormal, the AHR can be over-activated and this can contribute to breast cancer,” Novikov said. “We think that environmental pollutants that bind the AHR can both mimic this process of AHR activation and can also interfere with tryptophan metabolism itself, thus contributing to abnormal AHR activity in that way.”
Novikov, a student in the Superfund Research Program, will share the prize with her advisor, David Sherr, a professor of environmental health.
Since 1993, Sherr’s laboratory has conducted research on how common environmental pollutants, such as dioxins, polycyclic aromatic hydrocarbons, and PCBs, adversely affect the growth and behavior of several different types of normal and malignant cells. More recently, Sherr has focused on the molecular mechanisms that initiate and maintain breast cancer and on the effects of environmental chemicals on these processes. The laboratory has shown AHR plays an important role in the initiation and progression of human breast cancer.
The Graduate Research Symposium is a University-wide event open to all graduate students in a degree-granting program at BU, regardless of area of study. For nearly 20 years, the event has celebrated the scope of research being conducted by BU graduate students.
Said Novikov, “These studies can help develop evidence-based precautionary measures against harmful effects of environmental pollutants, as well as open new avenues for AHR and tryptophan metabolism-directed therapeutics and diagnostics.”
The Role of Endogenous and Environmental AHR Ligands in Mammary Epithelial Cell Tumor Growth and Invasion
Abstract: Historically, AHR activation by environmental ligands was seen to facilitate mutations through CYP1 up-regulation and mutagen production. Our findings suggested that AHR activity
drives cancer in the absence of environmental ligands without mutation. Our long-term goal is to identify endogenous ligands present in human mammary tumor cells, to determine how their production is controlled, and to assess how environmental AHR ligands alter this process. We hypothesize that metabolites produced by the kynurenine (KYN) pathway of tryptophan metabolism drive AHR activity and enforce invasion of breast cancer cells. As a corollary, we predict that environmental AHR ligands distort this signaling. We found that the tryptophan metabolites kynurenine (KYN) and xanthurenic acid (XA), both detected in Hs578T cell lysates, are potent AHR agonists. Hs578T cells highly express TDO, the rate-limiting enzyme in the kynurenine pathway. TDO knock-down reduced expression of Cyp1B1, a transcriptional target of the AHR, as well as the expression of invasion-related genes MMP1 and 9, cell migration in a wound healing assay, and invasive growth in Matrigel. We also found that AhR activity contributes to transcriptional regulation of TDO. Our results support the hypothesis that AHR, hyper-activated by endogenous ligands produced via the KYN pathway, contributes to the malignant phenotype in breast cancer. Moreover, our finding that the AHR transcriptionally regulates TDO expression leads us to propose that environmental AHR ligands lead to increased production of endogenous AHR ligands by up-regulating TDO in a positive feed-back loop and thereby enforcing AHR-driven cell malignancy.