Integrated Molecular Characterization to Reveal the Association between Kynurenine 3-Monooxygenase Expression and Tumorigenesis in Human Breast Cancers

Abstract

Kynurenine 3-monooxygenase (KMO) is overexpressed in several tumors and participates in the progression of breast cancer tumorigenesis, including cancer types such as triple-negative breast cancer (TNBC). This malignant gene is an enzyme in the kynurenine pathway, which is involved in the carcinogenesis of cancer through immune function manipulation. However, it remains unclear whether the role of the KMO contributes to tumorigenesis and immune functions in human breast cancer. In this study, we found that KMO was highly expressed in different types of tumors, especially in invasive ductal breast carcinoma. In addition, KMO expression was positively correlated with the malignant clinical features of patients with breast cancer, such as TNBC and a nodal-positive status, along with patients with a higher Nottingham prognostic index (NPI). Furthermore, the top ten KMO-correlated genes were the chemokines and pro-inflammatory cytokines known to be involved in the progression of various cancers, therefore, KMO may facilitate breast cancers via synergistically regulating inflammatory responses in tumors with these hub genes. Taken together, these findings highlight the tumor-promotion role of KMO in breast cancers and suggest that KMO can serve as a biomarker for prognosis prediction in breast cancer patients.

The Complex Dynamic of Phase I Drug Metabolism in the Early Stages of Doxorubicin Resistance in Breast Cancer Cells

“…Together with estrogen receptors and especially drug transporters, CYPs and Phase I oxidoreductases seem to be determinant in DR. This is due to their role in drug metabolism as well as a variety of pathways that regulate cell cycle and cell growth, which are normally associated with DR mechanisms and tumor progression [ 23 , 28 , 29 , 30 , 31 , 32 , 33 , 53 , 54 , 55 , 56 , 57 , 58 ]. However, it remains unclear whether the role of the Phase I enzymes contribute to the development of early stages of chemotherapy resistance in human BC, which may enable the formation of DR to therapeutic drug levels.…”

“…PAH might play a role in tumor progression, as it catalyzes the rate-limiting step in the phenylalanine catabolism, converting L-phenylalanine into L-tyrosine, two essential amino acids, whose uptake and metabolism are apparently part of cancer reprogramming [ 53 ]. Integrated into the kynurenine pathway, KMO has been described to be upregulated in BC patients, particularly in patients with aggressive malignant BC [ 32 , 55 ]. It has been correlated with deregulation of genes encoding chemokines and pro-inflammatory cytokines, known to be involved in the inflammatory aspect of tumorigenesis, but also in regulation of CYP expression and other DMEs [ 56 , 61 ].…”

“…Recently, the expression and activity profiles of several CYPs and oxidoreductases have been investigated as putative tumor biomarkers. The association between expression of these enzymes and cancer risk, tumorigenesis, progression, metastasis, and prognosis has been widely reported in basic, clinical and epidemiological studies [ 23 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 ]. Nevertheless, their role has not been properly established in the formation of DR.…”

Characterization of the Metabolome of Breast Tissues from Non-Hispanic Black and Non-Hispanic White Women Reveals Correlations between Microbial Dysbiosis and Enhanced Lipid Metabolism Pathways in Triple-Negative Breast Tumors

“…In a study by Kanaan et al, 3-fold greater Trp levels and a 7-fold and 8-fold increase in its metabolic intermediates in NAD+ biosynthesis, KYN and quinolinate, respectively [ 20 ] were reported, which is in agreement with our findings (data not shown). Furthermore, a positive correlation between the increased expression of enzymes involved in KYN metabolism, including kynurenine 3-monooxygenase (KMO), has been observed to play a role in TNBC metastasis and recurrence [ 21 ] and malignant phenotype in patients with TNBC [ 22 ]. Of interest, overexpression of KMO has been suggested to contribute to the malignant phenotype of TNBC cells, particularly cancer stem cell (CSC) properties, and 3) KMO-induced β-catenin stabilization, which also leads to increased expression of pluripotent genes such as Nanog, Oct4, and Sox2 [ 23 ].…”

Kynurenine‐3‐monooxygenase (KMO): From its biological functions to therapeutic effect in diseases progression

“…These T cells upregulate programmed cell death protein 1 (PD‐1) in an AHR‐dependent way, resulting in the immune evasion of tumor cells (Y. Liu et al, 2018). In addition, high levels of QA can stimulate NMDAR, initiate gene activation and cell proliferation and promote cell survival via the extracellular signal‐regulated kinase (ERK1/2) pathways (Tsang et al, 2021) (Figure 4). Due to the high expression of KMO promotes the proliferation, migration, and invasion of tumor cells, the upregulation of KMO gene is related to the poor prognosis of human HCC and breast cancer.…”