NYMC Student Theses and Dissertations

Date of Award

5-25-2025

Document Type

Master's Thesis - Open Access

Degree Name

Master of Science

Department

Pathology

First Advisor

Dr. Marina M. Holz

Second Advisor

Dr. Tetyana Cheairs

Third Advisor

Dr. Kenneth M. Lerea

Abstract

Breast cancer remains the second leading cause of death in women worldwide, with estrogen receptor (ER)-positive subtypes comprising over 70% of cases. Endocrine therapies, such as tamoxifen, are the primary treatment for ER-positive breast cancer; however, resistance inevitably develops, highlighting the need for alternative therapeutic strategies. Growing evidence suggests that the kynurenine pathway plays a significant role in breast cancer progression and metastasis. The kynurenine pathway metabolizes 95% of the amino acid tryptophan, generating metabolites such as kynurenine, kynurenic acid, 3-hydroxykynurenine, and ultimately Nicotinamide Adenine Dinucleotide (NAD). To better understand the impact of estrogen signaling on the kynurenine pathway, kynureninase expression of a key enzyme kynureninase (encoded by KYNU) was analyzed in MCF7 cells stimulated with estrogen, with and without tamoxifen treatment, using reverse transcription quantitative PCR (RT-qPCR) and Western blot analysis. The results showed that estrogen stimulation significantly downregulated kynureninase expression at both the mRNA and protein levels. In contrast, tamoxifen treatment prevented downstream ER signaling, as evidenced by increased kynureninase levels. These findings suggest that estrogen signaling through the ER suppresses KYNU expression, potentially contributing to a pro-tumorigenic environment in ER-positive breast cancer by accumulating upstream kynurenine pathway metabolites. These results could be a basis for further research into novel therapeutic strategies targeting the kynurenine pathway and improving outcomes for patients with ER-positive breast cancer.

Keywords

Breast cancer, Estrogen, Estrogen receptor, Kynurenine pathway, Kynureninase

Disciplines

Medicine and Health Sciences

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