Naringenin in Si-Ni-San Formula Inhibits Chronic Psychological Stress-induced Breast Cancer Growth and Metastasis by Modulating Estrogen Metabolism Through FXR/EST Pathway

Overview

Journal J Adv Res

Specialties General Medicine
Science

Date 2022 Jun 19

PMID 35718080

Authors

Juping Zhang

Neng Wang

Yifeng Zheng

Bowen Yang

Shengqi Wang

Xuan Wang

Bo Pan

Zhiyu Wang

Affiliations

Soon will be listed here.

Abstract

Introduction: Chronic psychological stress is a well-established risk factor for breast cancer development. Si-Ni-San (SNS) is a classical traditional Chinese medicine formula prescribed to psychological disorder patients. However, its action effects, molecular mechanisms, and bioactive phytochemicals against breast cancer are not yet clear.

Objectives: This study aimed to explore the modulatory mechanism and bioactive compound of SNS in regulating estrogen metabolism during breast cancer development induced by chronic psychological stress.

Methods: Mouse breast cancer xenograft was used to determine the effect of SNS on breast cancer growth and metastasis. Metabolomics analysis was conducted to discover the impact of SNS on metabolic profile changes in vivo. Multiple molecular biology experiments and breast cancer xenografts were applied to verify the anti-metastatic potentials of the screened bioactive compound.

Results: SNS remarkably inhibited chronic psychological stress-induced breast cancer growth and metastasis in the mouse breast cancer xenograft. Meanwhile, chronic psychological stress increased the level of cholic acid, accompanied by the elevation of estradiol. Mechanistic investigation demonstrated that cholic acid activated farnesoid X receptor (FXR) expression, which inhibited hepatocyte nuclear factor 4α (HNF4α)-mediated estrogen sulfotransferase (EST) transcription in hepatocytes, and finally resulting in estradiol elevation. Notably, SNS inhibited breast cancer growth by suppressing estradiol level via modulating FXR/EST signaling. Furthermore, luciferase-reporting gene assay screened naringenin as the most bioactive compound in SNS for triggering EST activity in hepatocytes. Interestingly, pharmacokinetic study revealed that naringenin had the highest absorption in the liver tissue. Following in vivo and in vitro studies demonstrated that naringenin inhibited stress-induced breast cancer growth and metastasis by promoting estradiol metabolism via FXR/EST signaling.

Conclusion: This study not only highlights FXR/EST signaling as a crucial target in mediating stress-induced breast cancer development, but also provides naringenin as a potential candidate for breast cancer endocrine therapy via promoting estradiol metabolism.

Citing Articles

Role, mechanisms and effects of in anti‑breast cancer (Review).

Jiang S, Li C, Liu D, Zeng F, Wei W, He T Oncol Lett. 2025; 29(4):166.

PMID: 39963320 PMC: 11831725. DOI: 10.3892/ol.2025.14912.

Naringenin induces ferroptosis in osteosarcoma cells through the STAT3-MGST2 signaling pathway.

Li Y, Bai X J Bone Oncol. 2025; 50():100657.

PMID: 39835176 PMC: 11743371. DOI: 10.1016/j.jbo.2024.100657.

Body Roundness Index Trajectories and the Risk of Cancer: A Cohort Study.

Chen Y, Wang Y, Zheng X, Liu T, Liu C, Lin S Cancer Med. 2024; 13(23):e70447.

PMID: 39606808 PMC: 11602755. DOI: 10.1002/cam4.70447.

Application of omics technologies in studies on antitumor effects of Traditional Chinese Medicine.

Tan P, Wei X, Huang H, Wang F, Wang Z, Xie J Chin Med. 2024; 19(1):123.

PMID: 39252074 PMC: 11385818. DOI: 10.1186/s13020-024-00995-x.

Natural products as inhibitors against pancreatic cancer cell proliferation and invasion: possible mechanisms.

Li X, Yang X, Guo W, Li H, Sun W, Lin X Am J Cancer Res. 2024; 14(6):2695-2713.

PMID: 39005683 PMC: 11236794. DOI: 10.62347/XLZX8935.

References

Hatkevich T, Ramos J, Santos-Sanchez I, Patel Y . A naringenin-tamoxifen combination impairs cell proliferation and survival of MCF-7 breast cancer cells. Exp Cell Res. 2014; 327(2):331-9. DOI: 10.1016/j.yexcr.2014.05.017. View

Cui B, Luo Y, Tian P, Peng F, Lu J, Yang Y . Stress-induced epinephrine enhances lactate dehydrogenase A and promotes breast cancer stem-like cells. J Clin Invest. 2019; 129(3):1030-1046. PMC: 6391112. DOI: 10.1172/JCI121685. View

Huang F, Zheng X, Ma X, Jiang R, Zhou W, Zhou S . Theabrownin from Pu-erh tea attenuates hypercholesterolemia via modulation of gut microbiota and bile acid metabolism. Nat Commun. 2019; 10(1):4971. PMC: 6823360. DOI: 10.1038/s41467-019-12896-x. View

Kodama S, Hosseinpour F, Goldstein J, Negishi M . Liganded pregnane X receptor represses the human sulfotransferase SULT1E1 promoter through disrupting its chromatin structure. Nucleic Acids Res. 2011; 39(19):8392-403. PMC: 3201858. DOI: 10.1093/nar/gkr458. View

Eliassen A, Spiegelman D, Xu X, Keefer L, Veenstra T, Barbieri R . Urinary estrogens and estrogen metabolites and subsequent risk of breast cancer among premenopausal women. Cancer Res. 2011; 72(3):696-706. PMC: 3271178. DOI: 10.1158/0008-5472.CAN-11-2507. View

Liu X, Xue R, Yang C, Gu J, Chen S, Zhang S . Cholestasis-induced bile acid elevates estrogen level via farnesoid X receptor-mediated suppression of the estrogen sulfotransferase SULT1E1. J Biol Chem. 2018; 293(33):12759-12769. PMC: 6102144. DOI: 10.1074/jbc.RA118.001789. View

Wen J, Yang L, Qin F, Zhao L, Xiong Z . An integrative UHPLC-MS/MS untargeted metabonomics combined with quantitative analysis of the therapeutic mechanism of Si-Ni-San. Anal Biochem. 2018; 567:128-135. DOI: 10.1016/j.ab.2018.10.023. View

MacNiven E, deCatanzaro D, Younglai E . Chronic stress increases estrogen and other steroids in inseminated rats. Physiol Behav. 1992; 52(1):159-62. DOI: 10.1016/0031-9384(92)90446-9. View

Sampson J, Falk R, Schairer C, Moore S, Fuhrman B, Dallal C . Association of Estrogen Metabolism with Breast Cancer Risk in Different Cohorts of Postmenopausal Women. Cancer Res. 2016; 77(4):918-925. PMC: 5313342. DOI: 10.1158/0008-5472.CAN-16-1717. View

10.

Sherstha R, McKinley C, Russ P, Scherzinger A, Bronner T, Showalter R . Postmenopausal estrogen therapy selectively stimulates hepatic enlargement in women with autosomal dominant polycystic kidney disease. Hepatology. 1997; 26(5):1282-6. DOI: 10.1002/hep.510260528. View

11.

Groenvold M, Petersen M, Idler E, Bjorner J, Fayers P, Mouridsen H . Psychological distress and fatigue predicted recurrence and survival in primary breast cancer patients. Breast Cancer Res Treat. 2007; 105(2):209-19. DOI: 10.1007/s10549-006-9447-x. View

12.

Wang F, Zhao C, Yang M, Zhang L, Wei R, Meng K . Four Citrus Flavanones Exert Atherosclerosis Alleviation Effects in ApoE Mice Different Metabolic and Signaling Pathways. J Agric Food Chem. 2021; 69(17):5226-5237. DOI: 10.1021/acs.jafc.1c01463. View

13.

Cao K, Shen C, Yuan Y, Bai S, Yang L, Guo L . SiNiSan Ameliorates the Depression-Like Behavior of Rats That Experienced Maternal Separation Through 5-HT1A Receptor/CREB/BDNF Pathway. Front Psychiatry. 2019; 10:160. PMC: 6447714. DOI: 10.3389/fpsyt.2019.00160. View

14.

Sobhani N, DAngelo A, Pittacolo M, Roviello G, Miccoli A, Corona S . Updates on the CDK4/6 Inhibitory Strategy and Combinations in Breast Cancer. Cells. 2019; 8(4). PMC: 6523967. DOI: 10.3390/cells8040321. View

15.

Silvennoinen R, Quesada H, Kareinen I, Julve J, Kaipiainen L, Gylling H . Chronic intermittent psychological stress promotes macrophage reverse cholesterol transport by impairing bile acid absorption in mice. Physiol Rep. 2015; 3(5). PMC: 4463831. DOI: 10.14814/phy2.12402. View

16.

Ciana P, Raviscioni M, Mussi P, Vegeto E, Que I, Parker M . In vivo imaging of transcriptionally active estrogen receptors. Nat Med. 2002; 9(1):82-6. DOI: 10.1038/nm809. View

17.

Ji X, Chen G, Song Y, Hua M, Wang L, Li L . Intratumoral estrogen sulfotransferase induction contributes to the anti-breast cancer effects of the dithiocarbamate derivative TM208. Acta Pharmacol Sin. 2015; 36(10):1246-55. PMC: 4814201. DOI: 10.1038/aps.2015.14. View

18.

Baumgartner N, Daniel J . Estrogen receptor α: a critical role in successful female cognitive aging. Climacteric. 2021; 24(4):333-339. PMC: 8273070. DOI: 10.1080/13697137.2021.1875426. View

19.

Sung H, Ferlay J, Siegel R, Laversanne M, Soerjomataram I, Jemal A . Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021; 71(3):209-249. DOI: 10.3322/caac.21660. View

20.

Wang S, Yuan X, Lu D, Guo L, Wu B . Farnesoid X receptor regulates SULT1E1 expression through inhibition of PGC1α binding to HNF4α. Biochem Pharmacol. 2017; 145:202-209. DOI: 10.1016/j.bcp.2017.08.023. View