Discovery of breast cancer risk genes and establishment of a prediction model based on estrogen metabolism regulation

Abstract

Background Multiple common variants identified by genome-wide association studies have shown limited evidence of the risk of breast cancer in Chinese individuals. In this study, we aimed to uncover the relationship between estrogen levels and the genetic polymorphism of estrogen metabolism-related enzymes in breast cancer (BC) and establish a risk prediction model composed of estrogen-metabolizing enzyme genes and GWAS-identified breast cancer-related genes based on a polygenic risk score. Methods Unrelated BC patients and healthy subjects were recruited for analysis of estrogen levels and single nucleotide polymorphisms (SNPs) in genes encoding estrogen metabolism-related enzymes. The polygenic risk score (PRS) was used to explore the combined effect of multiple genes, which was calculated using a Bayesian approach. An independent sample t-test was used to evaluate the differences between PRS scores of BC and healthy subjects. The discriminatory accuracy of the models was compared using the area under the receiver operating characteristic (ROC) curve. Results The estrogen homeostasis profile was disturbed in BC patients, with parent estrogens (E1, E2) and carcinogenic catechol estrogens (2/4-OHE1, 2-OHE2, 4-OHE2) significantly accumulating in the serum of BC patients. We then established a PRS model to evaluate the role of SNPs in multiple genes. PRS model 1 (M1) was established from SNPs in 6 GWAS-identified high risk genes. On the basis of M1, we added SNPs from 7 estrogen metabolism enzyme genes to establish PRS model 2 (M2). The independent sample t-test results showed that there was no difference between BC and healthy subjects in M1 (P = 0.17); however, there was a significant difference between BC and healthy subjects in M2 (P = 4.9*10− 5). The ROC curve results showed that the accuracy of M2 (AUC = 62.18%) in breast cancer risk identification was better than that of M1 (AUC = 54.56%). Conclusion Estrogen and related metabolic enzyme gene polymorphisms are closely related to BC. The model constructed by adding estrogen metabolic enzyme gene SNPs has a good predictive ability for breast cancer risk, and the accuracy is greatly improved compared with that of the PRS model that only includes GWAS-identified gene SNPs.

CYP1B1-catalyzed 4-OHE2 promotes the castration resistance of prostate cancer stem cells by estrogen receptor α-mediated IL6 activation

“…CYP1B1 (cytochrome P450, family 1, subfamily B, polypeptide 1) is an enzyme that catalyzes 17β-estradiol to 4-OHE2 [ 25 ]. CYP1B1 is abnormally highly expressed in a variety of cancers (e.g., breast cancer, head and neck cancer, and PCa), and its effect on reducing the drug sensitivity of tumor cells has been widely reported [ 26 – 28 ].…”

SCARB1 in extracellular vesicles promotes NPC metastasis by co-regulating M1 and M2 macrophage function

“…HAAO has been reported to be associated with endometrial cancer and prostate cancer, but it has not been reported in NPC. CYP1B1 (cytochrome P450, family 1, subfamily B, polypeptide 1) is an enzyme that catalyzes the conversion of 17β-estradiol into 4-OHE2 [ 40 ]. CYP1B1 is abnormally highly expressed in various cancers in various cancers (e.g., breast, head and neck cancers and prostate cancer) [ 41 – 43 ].…”

Functional variant rs10175368 which affects the expression of CYP1B1 plays a protective role against breast cancer in a Chinese Han population

“…eQTL, expression quantitative trait loci. enzyme function, in lower levels of 4-OH-E2 and lower corresponding adduct production, thereby reducing breast cancer risk (Qiu et al, 2018;Zhao et al, 2021).…”

“…Cytochrome P450 1B1 (CYP1B1), a member of the second subfamily of cytochrome P450 family I, is a crucial metabolic enzyme in humans ( Cavalieri and Rogan, 2006 ), and high expression levels of CYP1B1 were found in breast, ovarian, and uterine tissues ( Saini et al ., 2009 ; Min et al ., 2022 ). As a critical factor in the initiation and development of hormone-related malignancies, CYP1B1 catalyzes the conversion of 17-estradiol to 4-hydroxylated estradiol (4-OH-E2), thus playing a central role in estrogen metabolism ( Gajjar et al ., 2012 ; Zhao et al ., 2021 ). In breast cancer, 4-OH-E2 goes through a redox cycle that results in the production of oxides as well as chemically reactive estrogenic semiquinone and quinone intermediates (e.g.…”