Significant limitations of the reactive medical approach in breast cancer management are clearly reflected by alarming statistics recorded worldwide. According to the WHO updates, breast malignancies become the leading cancer type. Further, the portion of premenopausal breast cancer cases is permanently increasing and demonstrates particularly aggressive patterns and poor outcomes exemplified by young patients with triple-negative breast cancer that lacks targeted therapy. Accumulating studies suggest the crucial role of stem cells in tumour biology, high metastatic activity, and therapy resistance of aggressive breast cancer. Therefore, targeting breast cancer stem cells is a promising treatment approach in secondary and tertiary breast cancer care. To this end, naturally occurring substances demonstrate high potential to target cancer stem cells which, however, require in-depth analysis to identify effective anti-cancer agents for cost-effective breast cancer management. The current article highlights the properties of flavonoids particularly relevant for targeting breast cancer stem cells to mitigate therapy resistance. The proposed approach is conformed with the principles of 3P medicine by applying predictive diagnostics, patient stratification and treatments tailored to the individualised patient profile. Expected impacts are very high, namely, to overcome limitations of reactive medical services improving individual outcomes and the healthcare economy in breast cancer management. Relevant clinical applications are exemplified in the paper.

Clinic of Obstetrics and Gynecology Jessenius Faculty of Medicine Comenius University in Bratislava Martin Slovakia

Department of Anatomy Jessenius Faculty of Medicine Comenius University in Bratislava Martin Slovakia

Department of Applied Ecology Faculty of Environmental Sciences Czech University of Life Sciences Prague Prague Czechia

Department of Medical Biology Jessenius Faculty of Medicine Comenius University in Bratislava Martin Slovakia

Department of Pathological Physiology Jessenius Faculty of Medicine Comenius University in Bratislava Martin Slovakia

Department of Pharmacology Faculty of Medicine Pavol Jozef Safarik University Kosice Slovakia

Department of Physiology and Biophysics Weill Cornell Medicine in Qatar Qatar Foundation Doha Qatar

Museum of Literature in Moravia Rajhrad Czechia

Predictive Preventive and Personalised Medicine Department of Radiation Oncology University Hospital Bonn Rheinische Friedrich Wilhelms Universität Bonn Bonn Germany

Zobrazit více v PubMed

Abotaleb M., Samuel S. M., Varghese E., Varghese S., Kubatka P., Liskova A., et al. (2018), Flavonoids in cancer and apoptosis. Cancers (Basel) 11. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6357032/. PubMed PMC

Ambrose J. M., Veeraraghavan V. P., Vennila R., Rupert S., Sathyanesan J., Meenakshisundaram R., et al. (2022). Comparison of mammosphere formation from stem-like cells of normal breast, malignant primary breast tumors, and MCF-7 cell line. J. Egypt. Natl. Cancer Inst. 34, 51. 10.1186/s43046-022-00152-1 PubMed DOI

Arif K., Hussain I., Rea C., El-Sheemy M. (2015). The role of Nanog expression in tamoxifen-resistant breast cancer cells. Onco Targets Ther. 8, 1327–1334. 10.2147/OTT.S67835 PubMed DOI PMC

Arnold M., Morgan E., Rumgay H., Mafra A., Singh D., Laversanne M., et al. (2022). Current and future burden of breast cancer: Global statistics for 2020 and 2040. Breast 66, 15–23. 10.1016/j.breast.2022.08.010 PubMed DOI PMC

Arnouk H., Yum G., Shah D. (2021). Cripto-1 as a key factor in tumor progression, epithelial to mesenchymal transition and cancer stem cells. Int. J. Mol. Sci. 22, 9280. 10.3390/ijms22179280 PubMed DOI PMC

Bhandary L., Bailey P. C., Chang K. T., Underwood K. F., Lee C. J., Whipple R. A., et al. (2021). Lipid tethering of breast tumor cells reduces cell aggregation during mammosphere formation. Sci. Rep. Nat. Publ. Group 11, 3214. 10.1038/s41598-021-81919-9 PubMed DOI PMC

Bie B., Sun J., Guo Y., Li J., Jiang W., Yang J., et al. (2017). Baicalein: A review of its anti-cancer effects and mechanisms in hepatocellular carcinoma. Biomed. Pharmacother. 93, 1285–1291. 10.1016/j.biopha.2017.07.068 PubMed DOI

Bourguignon L. Y. W., Peyrollier K., Xia W., Gilad E. (2008). Hyaluronan-CD44 interaction activates stem cell marker nanog, stat-3-mediated MDR1 gene expression, and ankyrin-regulated multidrug efflux in breast and ovarian tumor cells. J. Biol. Chem. 283, 17635–17651. 10.1074/jbc.M800109200 PubMed DOI PMC

Britton K. M., Kirby J. A., Lennard T. W. J., Meeson A. P. (2011). Cancer stem cells and side population cells in breast cancer and metastasis. Cancers (Basel) 3, 2106–2130. 10.3390/cancers3022106 PubMed DOI PMC

Bubnov R., Polivka J., Zubor P., Konieczka K., Golubnitschaja O. (2017). Pre-metastatic niches” in breast cancer: Are they created by or prior to the tumour onset? “Flammer syndrome” relevance to address the question. EPMA J. 8, 141–157. 10.1007/s13167-017-0092-8 PubMed DOI PMC

Calderón-Montaño J. M., Burgos-Morón E., Pérez-Guerrero C., López-Lázaro M. (2011). A review on the dietary flavonoid kaempferol. Mini Rev. Med. Chem. 11, 298–344. 10.2174/138955711795305335 PubMed DOI

Colamba Pathiranage V., Lowe J. N., Rajagopalan U., Ediriweera M. K., Senathilake K., Piyathilaka P., et al. (2021). Hexane extract of Garcinia quaesita fruits induces apoptosis in breast cancer stem cells isolated from triple negative breast cancer cell line MDA-MB-231. Nutr. Cancer 73, 845–855. 10.1080/01635581.2020.1773511 PubMed DOI

Crew K. D., Ho K. A., Brown P., Greenlee H., Bevers T. B., Arun B., et al. (2015). Effects of a green tea extract, Polyphenon E, on systemic biomarkers of growth factor signalling in women with hormone receptor-negative breast cancer. J. Hum. Nutr. Diet. 28, 272–282. 10.1111/jhn.12229 PubMed DOI PMC

Dong Z. (2016). Function of sirtuins in cancer stem cells. Int. J. Stem Cell Res. Ther. 3, 10.23937/2469-570x/1410024 DOI

Eng Q. Y., Thanikachalam P. V., Ramamurthy S. (2018). Molecular understanding of Epigallocatechin gallate (EGCG) in cardiovascular and metabolic diseases. J. Ethnopharmacol. 210, 296–310. 10.1016/j.jep.2017.08.035 PubMed DOI

Ercan C., van Diest P. J., Vooijs M. (2011). Mammary development and breast cancer: The role of stem cells. Curr. Mol. Med. 11, 270–285. 10.2174/156652411795678007 PubMed DOI PMC

Esquer H., Zhou Q., Abraham A. D., LaBarbera D. V. (2020). Advanced high-content-screening applications of clonogenicity in cancer. SLAS Discov. 25, 734–743. 10.1177/2472555220926921 PubMed DOI

Fan P., Fan S., Wang H., Mao J., Shi Y., Ibrahim M. M., et al. (2013). Genistein decreases the breast cancer stem-like cell population through Hedgehog pathway. Stem Cell Res. Ther. 4, 146. 10.1186/scrt357 PubMed DOI PMC

Fröhlich H., Patjoshi S., Yeghiazaryan K., Kehrer C., Kuhn W., Golubnitschaja O. (2018). Premenopausal breast cancer: Potential clinical utility of a multi-omics based machine learning approach for patient stratification. EPMA J. 9, 175–186. 10.1007/s13167-018-0131-0 PubMed DOI PMC

Galoczova M., Coates P., Vojtesek B. (2018). STAT3, stem cells, cancer stem cells and p63. Cell Mol. Biol. Lett. 23, 12. 10.1186/s11658-018-0078-0 PubMed DOI PMC

Gao F., Huang G., Xiao J. (2020). Chalcone hybrids as potential anticancer agents: Current development, mechanism of action, and structure-activity relationship. Med. Res. Rev. 40, 2049–2084. 10.1002/med.21698 PubMed DOI

Giró-Perafita A., Rabionet M., Planas M., Feliu L., Ciurana J., Ruiz-Martínez S., et al. (2019). EGCG-derivative G28 shows high efficacy inhibiting the mammosphere-forming capacity of sensitive and resistant TNBC models. Molecules 24, 1027. 10.3390/molecules24061027 PubMed DOI PMC

Giró-Perafita A., Sarrats A., Pérez-Bueno F., Oliveras G., Buxó M., Brunet J., et al. (2017). Fatty acid synthase expression and its association with clinico-histopathological features in triple-negative breast cancer. Oncotarget 8, 74391–74405. 10.18632/oncotarget.20152 PubMed DOI PMC

Goldstein E., Yeghiazaryan K., Ahmad A., Giordano F. A., Fröhlich H., Golubnitschaja O. (2020). Optimal multiparametric set-up modelled for best survival outcomes in palliative treatment of liver malignancies: Unsupervised machine learning and 3 PM recommendations. EPMA J. 11, 505–515. 10.1007/s13167-020-00221-2 PubMed DOI PMC

Golubnitschaja O. (2017). Feeling cold and other underestimated symptoms in breast cancer: Anecdotes or individual profiles for advanced patient stratification? EPMA J. 8, 17–22. 10.1007/s13167-017-0086-6 PubMed DOI PMC

Golubnitschaja O., Liskova A., Koklesova L., Samec M., Biringer K., Büsselberg D., et al. (2021). Caution, “normal” BMI: Health risks associated with potentially masked individual underweight-EPMA position paper 2021. EPMA J. 1–22, 243–264. 10.1007/s13167-021-00251-4 PubMed DOI PMC

Guo X., Cai Q., Bao P., Wu J., Wen W., Ye F., et al. (2016). Long-term soy consumption and tumor tissue microRNA and gene expression in triple negative breast cancer. Cancer 122, 2544–2551. 10.1002/cncr.29981 PubMed DOI PMC

Han J. M., Kim H. L., Jung H. J. (2021). Ampelopsin inhibits cell proliferation and induces apoptosis in HL60 and K562 leukemia cells by downregulating AKT and NF-κB signaling pathways. Int. J. Mol. Sci. 22, 4265. 10.3390/ijms22084265 PubMed DOI PMC

Harish V., Haque E., Śmiech M., Taniguchi H., Jamieson S., Tewari D., et al. (2021). Xanthohumol for human malignancies: Chemistry, pharmacokinetics and molecular targets. Int. J. Mol. Sci. 22, 4478. 10.3390/ijms22094478 PubMed DOI PMC

Hermawan A., Ikawati M., Jenie R. I., Khumaira A., Putri H., Nurhayati I. P., et al. (2021). Identification of potential therapeutic target of naringenin in breast cancer stem cells inhibition by bioinformatics and in vitro studies. Saudi Pharm. J. 29, 12–26. 10.1016/j.jsps.2020.12.002 PubMed DOI PMC

Hero T., Bühler H., Kouam P. N., Priesch-Grzeszowiak B., Lateit T., Adamietz I. A. (2019). The triple-negative breast cancer cell line MDA-MB 231 is specifically inhibited by the ionophore salinomycin. Anticancer research. Int. Inst. Anticancer Res. 39, 2821–2827. 10.21873/anticanres.13410 PubMed DOI

Howard F. M., Olopade O. I. (2021). Epidemiology of triple-negative breast cancer: A review. Cancer J. 27, 8–16. 10.1097/PPO.0000000000000500 PubMed DOI

Imran M., Rauf A., Abu-Izneid T., Nadeem M., Shariati M. A., Khan I. A., et al. (2019). Luteolin, a flavonoid, as an anticancer agent: A review. Biomed. Pharmacother. 112, 108612. 10.1016/j.biopha.2019.108612 PubMed DOI

Jasek K., Kubatka P., Samec M., Liskova A., Smejkal K., Vybohova D., et al. (2019). DNA methylation status in cancer disease: Modulations by plant-derived natural compounds and dietary interventions. Biomolecules 9, 289. 10.3390/biom9070289 PubMed DOI PMC

Jia D., Tan Y., Liu H., Ooi S., Li L., Wright K., et al. (2016). Cardamonin reduces chemotherapy-enriched breast cancer stem-like cells in vitro and in vivo . Oncotarget 7, 771–785. 10.18632/oncotarget.5819 PubMed DOI PMC

Kalyanaraman A., Gnanasampanthapandian D., Shanmughan P., Kishore P., Ramalingam S., Arunachalam R., et al. (2020). Tamoxifen induces stem-like phenotypes and multidrug resistance by altering epigenetic regulators in ERα+ breast cancer cells. Stem Cell Investig. 7, 20. 10.21037/sci-2020-020 PubMed DOI PMC

Kamble D., Mahajan M., Dhat R., Sitasawad S. (2021). Keap1-Nrf2 pathway regulates ALDH and contributes to radioresistance in breast cancer stem cells. Cells. Multidiscip. Digit. Publ. Inst. 10, 83. PubMed PMC

Kapinova A., Kubatka P., Liskova A., Baranenko D., Kruzliak P., Matta M., et al. (2019). Controlling metastatic cancer: The role of phytochemicals in cell signaling. J. Cancer Res. Clin. Oncol. 145, 1087–1109. 10.1007/s00432-019-02892-5 PubMed DOI

Kapinova A., Stefanicka P., Kubatka P., Zubor P., Uramova S., Kello M., et al. (2017). Are plant-based functional foods better choice against cancer than single phytochemicals? A critical review of current breast cancer research. Biomed. Pharmacother. 96, 1465–1477. 10.1016/j.biopha.2017.11.134 PubMed DOI

Karbasforooshan H., Hosseini S., Elyasi S., Fani Pakdel A., Karimi G. (2019). Topical silymarin administration for prevention of acute radiodermatitis in breast cancer patients: A randomized, double-blind, placebo-controlled clinical trial. Phytother. Res. 33, 379–386. 10.1002/ptr.6231 PubMed DOI

Khan S. A., Chatterton R. T., Michel N., Bryk M., Lee O., Ivancic D., et al. (2012). Soy isoflavone supplementation for breast cancer risk reduction: A randomized phase II trial. Cancer Prev. Res. (Phila). 5, 309–319. 10.1158/1940-6207.CAPR-11-0251 PubMed DOI PMC

Kim J. K., Park S. U. (2018). Quercetin and its role in biological functions: An updated review. EXCLI J. 17, 856–863. 10.17179/excli2018-1538 PubMed DOI PMC

Kim J. K., Park S. U. (2020). Recent studies on kaempferol and its biological and pharmacological activities. EXCLI J. 19, 627–634. PubMed PMC

Ko K-P., Kim S-W., Ma S. H., Park B., Ahn Y., Lee J. W., et al. (2013). Dietary intake and breast cancer among carriers and noncarriers of BRCA mutations in the Korean Hereditary Breast Cancer Study. Am. J. Clin. Nutr. 98, 1493–1501. 10.3945/ajcn.112.057760 PubMed DOI

Ko Y. S., Jin H., Lee J. S., Park S. W., Chang K. C., Kang K. M., et al. (2018). Radioresistant breast cancer cells exhibit increased resistance to chemotherapy and enhanced invasive properties due to cancer stem cells, Oncol. Rep. 40 (6), 3752–3762. 10.3892/or.2018.6714 PubMed DOI

Ko Y. S., Jung E. J., Go S-I., Jeong B. K., Kim G. S., Jung J-M., et al. (2020). Polyphenols extracted from Artemisia annua L. Exhibit anti-cancer effects on radio-resistant MDA-MB-231 human breast cancer cells by suppressing stem cell phenotype, β-catenin, and MMP-9. Molecules 25, 1916. 10.3390/molecules25081916 PubMed DOI PMC

Koh S. Y., Moon J. Y., Unno T., Cho S. K. (2019). Baicalein suppresses stem cell-like characteristics in radio- and chemoresistant MDA-MB-231 human breast cancer cells through up-regulation of IFIT2. Nutrients 11. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6471144/ . PubMed PMC

Koklesova L., Liskova A., Samec M., Zhai K., Al-Ishaq R. K., Bugos O., et al. (2021). Protective effects of flavonoids against mitochondriopathies and associated pathologies: Focus on the predictive approach and personalized prevention. Int. J. Mol. Sci. 22, 8649. 10.3390/ijms22168649 PubMed DOI PMC

Koklesova L., Mazurakova A., Samec M., Kudela E., Biringer K., Kubatka P., et al. (2022). Mitochondrial health quality control: Measurements and interpretation in the framework of predictive, preventive, and personalized medicine. EPMA J. 13, 177–193. 10.1007/s13167-022-00281-6 PubMed DOI PMC

Kotiyal S., Bhattacharya S. (2014). Breast cancer stem cells, EMT and therapeutic targets. Biochem. Biophysical Res. Commun. 453, 112–116. 10.1016/j.bbrc.2014.09.069 PubMed DOI

Kubatka P., Kapinová A., Kello M., Kruzliak P., Kajo K., Výbohová D., et al. (2016). Fruit peel polyphenols demonstrate substantial anti-tumour effects in the model of breast cancer. Eur. J. Nutr. 55, 955–965. 10.1007/s00394-015-0910-5 PubMed DOI

Kubatka P., Kapinová A., Kružliak P., Kello M., Výbohová D., Kajo K., et al. (2015). Antineoplastic effects of Chlorella pyrenoidosa in the breast cancer model. Nutrition 31, 560–569. 10.1016/j.nut.2014.08.010 PubMed DOI

Kubatka P., Kello M., Kajo K., Samec M., Jasek K., Vybohova D., et al. (2020). Chemopreventive and therapeutic efficacy of Cinnamomum zeylanicum L. bark in experimental breast carcinoma: Mechanistic in vivo and in vitro analyses. Molecules 25 (6),1399. 10.3390/molecules25061399 PubMed DOI PMC

Kubatka P., Kello M., Kajo K., Samec M., Liskova A., Jasek K., et al. (2020). Rhus coriaria L. (Sumac) demonstrates oncostatic activity in the therapeutic and preventive model of breast carcinoma. Int. J. Mol. Sci. 22, 183. 10.3390/ijms22010183 PubMed DOI PMC

Kubatka P., Mazurakova A., Samec M., Koklesova L., Zhai K., Al-Ishaq R., et al. (2021). Flavonoids against non-physiologic inflammation attributed to cancer initiation, development, and progression-3PM pathways. EPMA J. 12, 559–587. 10.1007/s13167-021-00257-y PubMed DOI PMC

Kubatka P., Uramova S., Kello M., Kajo K., Kruzliak P., Mojzis J., et al. (2017). Antineoplastic effects of clove buds (Syzygium aromaticum L.) in the model of breast carcinoma. J. Cell Mol. Med. 21, 2837–2851. 10.1111/jcmm.13197 PubMed DOI PMC

Kudela E., Samec M., Kubatka P., Nachajova M., Laucekova Z., Liskova A., et al. (2019). Breast cancer in young women: Status quo and advanced disease management by a predictive, preventive, and personalized approach. Cancers (Basel) 11. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6896106/ . PubMed PMC

Lagadec C., Vlashi E., Della Donna L., Dekmezian C., Pajonk F. (2012). Radiation-induced reprogramming of breast cancer cells. Stem Cells 30, 833–844. 10.1002/stem.1058 PubMed DOI PMC

Lazzeroni M., Guerrieri-Gonzaga A., Gandini S., Johansson H., Serrano D., Cazzaniga M., et al. (2017). A presurgical study of lecithin formulation of green tea extract in women with early breast cancer. Cancer Prev. Res. (Phila). 10, 363–370. 10.1158/1940-6207.CAPR-16-0298 PubMed DOI

Li H., Li Q., Liu Z., Yang K., Chen Z., Cheng Q., et al. (2017). The versatile effects of dihydromyricetin in health. Evid. Based Complement. Altern. Med. 2017, 1053617. 10.1155/2017/1053617 PubMed DOI PMC

Li S., Zhao Q., Wang B., Yuan S., Wang X., Li K. (2018). Quercetin reversed MDR in breast cancer cells through down-regulating P-gp expression and eliminating cancer stem cells mediated by YB-1 nuclear translocation. Phytother. Res. 32, 1530–1536. 10.1002/ptr.6081 PubMed DOI

Li W., Xiao H. (2021). Dihydromyricetin alleviates high glucose-induced oxidative stress and apoptosis in human retinal pigment epithelial cells by downregulating miR-34a expression</p>, 14. DMSO. Dove Press, 387–397. PubMed PMC

Li Y-W., Xu J., Zhu G-Y., Huang Z-J., Lu Y., Li X-Q., et al. (2018). Apigenin suppresses the stem cell-like properties of triple-negative breast cancer cells by inhibiting YAP/TAZ activity. Cell Death Discov. 4, 105. 10.1038/s41420-018-0124-8 PubMed DOI PMC

Liskova A., Koklesova L., Samec M., Smejkal K., Samuel S. M., Varghese E., et al. (2020). Flavonoids in cancer metastasis. Cancers (Basel) [Internet]. 2020 [cited 2020 Oct 24];12. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352928/ . PubMed PMC

Liskova A., Koklesova L., Samec M., Varghese E., Abotaleb M., Samuel S. M., et al. (2020). Implications of flavonoids as potential modulators of cancer neovascularity. J. Cancer Res. Clin. Oncol. 146, 3079–3096. 10.1007/s00432-020-03383-8 PubMed DOI

Liskova A., Kubatka P., Samec M., Zubor P., Mlyncek M., Bielik T., et al. (2019). Dietary phytochemicals targeting cancer stem cells. Molecules 24. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6429493/ . PubMed PMC

Liskova A., Samec M., Koklesova L., Brockmueller A., Zhai K., Abdellatif B., et al. (2021). Flavonoids as an effective sensitizer for anti-cancer therapy: Insights into multi-faceted mechanisms and applicability towards individualized patient profiles. EPMA J. 12, 155–176. 10.1007/s13167-021-00242-5 PubMed DOI PMC

Liskova A., Stefanicka P., Samec M., Smejkal K., Zubor P., Bielik T., et al. (2020). Dietary phytochemicals as the potential protectors against carcinogenesis and their role in cancer chemoprevention. Clin. Exp. Med. 20, 173–190. 10.1007/s10238-020-00611-w PubMed DOI

Liu M., Yin H., Qian X., Dong J., Qian Z., Miao J. (2016). Xanthohumol, a prenylated chalcone from hops, inhibits the viability and stemness of doxorubicin-resistant MCF-7/ADR cells. Molecules 22, 36. 10.3390/molecules22010036 PubMed DOI PMC

Lu L-J. W., Chen N-W., Brunder D. G., Nayeem F., Nagamani M., Nishino T. K., et al. (2022). Soy isoflavones decrease fibroglandular breast tissue measured by magnetic resonance imaging in premenopausal women: A 2-year randomized double-blind placebo controlled clinical trial. Clin. Nutr. ESPEN 52, 158–168. 10.1016/j.clnesp.2022.10.007 PubMed DOI PMC

Luo M., Brooks M., Wicha M. S. (2015). Epithelial-mesenchymal plasticity of breast cancer stem cells: Implications for metastasis and therapeutic resistance. Curr. Pharm. Des. 21, 1301–1310. 10.2174/1381612821666141211120604 PubMed DOI PMC

Manupati K., Dhoke N. R., Debnath T., Yeeravalli R., Guguloth K., Saeidpour S., et al. (2017). Inhibiting epidermal growth factor receptor signalling potentiates mesenchymal-epithelial transition of breast cancer stem cells and their responsiveness to anticancer drugs. FEBS J. 284, 1830–1854. 10.1111/febs.14084 PubMed DOI

Mauro-Lizcano M., Sotgia F., Lisanti M. P. (2022). SOX2-high cancer cells exhibit an aggressive phenotype, with increases in stemness, proliferation and invasion, as well as higher metabolic activity and ATP production. Aging (Albany NY) 14, 9877–9889. 10.18632/aging.204452 PubMed DOI PMC

Mazurakova A., Koklesova L., Samec M., Kudela E., Kajo K., Skuciova V., et al. (2022). Anti-breast cancer effects of phytochemicals: Primary, secondary, and tertiary care. EPMA J. 13, 315–334. 10.1007/s13167-022-00277-2 PubMed DOI PMC

Mazurakova A., Koklesova L., Samec M., Kudela E., Sivakova J., Pribulova T., et al. (2022). Flavonoids exert potential in the management of hypertensive disorders in pregnancy. Pregnancy Hypertens. 29, 72–85. 10.1016/j.preghy.2022.06.007 PubMed DOI

Mazurakova A., Samec M., Koklesova L., Biringer K., Kudela E., Al-Ishaq R. K., et al. (2022). Anti-prostate cancer protection and therapy in the framework of predictive, preventive and personalised medicine - comprehensive effects of phytochemicals in primary, secondary and tertiary care. EPMA J. 13, 461–486. 10.1007/s13167-022-00288-z PubMed DOI PMC

Murota K., Nakamura Y., Uehara M. (2018). Flavonoid metabolism: The interaction of metabolites and gut microbiota. Biosci. Biotechnol. Biochem. 82, 600–610. 10.1080/09168451.2018.1444467 PubMed DOI

Nagle D. G., Ferreira D., Zhou Y-D. (2006). Epigallocatechin-3-gallate (EGCG): Chemical and biomedical perspectives. Phytochemistry 67, 1849–1855. 10.1016/j.phytochem.2006.06.020 PubMed DOI PMC

Nallanthighal S., Elmaliki K. M., Reliene R. (2017). Pomegranate extract alters breast cancer stem cell properties in association with inhibition of epithelial-to-mesenchymal transition. Nutr. Cancer 69, 1088–1098. 10.1080/01635581.2017.1359318 PubMed DOI

Nandi S. K., Pradhan A., Das B., Das B., Basu S., Mallick B., et al. (2022). Kaempferol attenuates viability of ex-vivo cultured post-NACT breast tumor explants through downregulation of p53 induced stemness, inflammation and apoptosis evasion pathways. Pathol. Res. Pract. 237, 154029. 10.1016/j.prp.2022.154029 PubMed DOI

Nandi S. K., Roychowdhury T., Chattopadhyay S., Basu S., Chatterjee K., Choudhury P., et al. (2022). Deregulation of the CD44-NANOG-MDR1 associated chemoresistance pathways of breast cancer stem cells potentiates the anti-cancer effect of Kaempferol in synergism with Verapamil. Toxicol. Appl. Pharmacol. 437, 115887. 10.1016/j.taap.2022.115887 PubMed DOI

Nawaz J., Rasul A., Shah M. A., Hussain G., Riaz A., Sarfraz I., et al. (2020). Cardamonin: A new player to fight cancer via multiple cancer signaling pathways. Life Sci. 250, 117591. 10.1016/j.lfs.2020.117591 PubMed DOI

Naz S., Imran M., Rauf A., Orhan I. E., Shariati M. A., et al. Iahtisham-Ul-Haq null (2019). Chrysin: Pharmacological and therapeutic properties. Life Sci. 235, 116797. 10.1016/j.lfs.2019.116797 PubMed DOI

Ninomiya M., Koketsu M. (2013). “Minor flavonoids (chalcones, flavanones, dihydrochalcones, and aurones),” in Natural products: Phytochemistry, botany and metabolism of alkaloids, phenolics and terpenes [internet]. Editors Ramawat K. G., Mérillon J-M. (Berlin, Heidelberg: Springer; ), 1867–1900. 10.1007/978-3-642-22144-6_62 DOI

Novak D., Hüser L., Elton J. J., Umansky V., Altevogt P., Utikal J. (2020). SOX2 in development and cancer biology. Seminars Cancer Biol. 67, 74–82. 10.1016/j.semcancer.2019.08.007 PubMed DOI

O’Callaghan C., Vassilopoulos A. (2017). Sirtuins at the crossroads of stemness, aging, and cancer. Aging Cell 16, 1208–1218. 10.1111/acel.12685 PubMed DOI PMC

Ouyang Y., Li J., Chen X., Fu X., Sun S., Wu Q. (2021). Chalcone derivatives: Role in anticancer therapy. Biomolecules 11, 894. 10.3390/biom11060894 PubMed DOI PMC

Panche A. N., Diwan A. D., Chandra S. R. (2016). Flavonoids: An overview. J. Nutr. Sci. [Internet] 5. PubMed PMC

Patel J. R., Gallegos K. M., Walker R. R., Davidson A. M., Davenport I., Tilghman S. L. (2021). Mammospheres of letrozole-resistant breast cancer cells enhance breast cancer aggressiveness. Oncol. Lett. 22, 620. 10.3892/ol.2021.12881 PubMed DOI PMC

Pham P. V., Phan N. L. C., Nguyen N. T., Truong N. H., Duong T. T., Le D. V., et al. (2011). Differentiation of breast cancer stem cells by knockdown of CD44: Promising differentiation therapy. J. Transl. Med. 9, 209. 10.1186/1479-5876-9-209 PubMed DOI PMC

Qin S., He X., Lin H., Schulte B. A., Zhao M., Tew K. D., et al. (2021). Nrf2 inhibition sensitizes breast cancer stem cells to ionizing radiation via suppressing DNA repair. Free Radic. Biol. Med. 169, 238–247. 10.1016/j.freeradbiomed.2021.04.006 PubMed DOI PMC

Rajendran V., Jain M. V. (2018). In vitro tumorigenic assay: Colony forming assay for cancer stem cells. Methods Mol. Biol. 1692, 89–95. 10.1007/978-1-4939-7401-6_8 PubMed DOI

Ryoo I-G., Choi B-H., Kwak M-K. (2015). Activation of NRF2 by p62 and proteasome reduction in sphere-forming breast carcinoma cells. Oncotarget 6, 8167–8184. 10.18632/oncotarget.3047 PubMed DOI PMC

Salehi B., Fokou P. V. T., Sharifi-Rad M., Zucca P., Pezzani R., Martins N., et al. (2019). The therapeutic potential of naringenin: A review of clinical trials. Pharm. (Basel) 12, E11. 10.3390/ph12010011 PubMed DOI PMC

Salehi B., Machin L., Monzote L., Sharifi-Rad J., Ezzat S. M., Salem M. A., et al. (2020). Therapeutic potential of quercetin: New insights and perspectives for human health. ACS Omega 5, 11849–11872. 10.1021/acsomega.0c01818 PubMed DOI PMC

Samec M., Liskova A., Koklesova L., Mersakova S., Strnadel J., Kajo K., et al. (2021)., .Flavonoids targeting HIF-1: Implications on cancer metabolism. Multidiscip. Digit. Publ. Inst. 13, 130 PubMed PMC

Sansone P., Savini C., Kurelac I., Chang Q., Amato L. B., Strillacci A., et al. (2017). Packaging and transfer of mitochondrial DNA via exosomes regulate escape from dormancy in hormonal therapy-resistant breast cancer. Proc. Natl. Acad. Sci. U. S. A. 114, E9066–E9075. 10.1073/pnas.1704862114 PubMed DOI PMC

Sharifi-Rad J., Quispe C., Imran M., Rauf A., Nadeem M., Gondal T. A., et al. (2021). Genistein: An integrative overview of its mode of action, pharmacological properties, and health benefits. Oxid. Med. Cell Longev. 2021, 3268136. 10.1155/2021/3268136 PubMed DOI PMC

Sharma A., Sinha S., Keswani H., Shrivastava N. (2022). Kaempferol and Apigenin suppresses the stemness properties of TNBC cells by modulating Sirtuins. Mol. Divers 26, 3225–3240. 10.1007/s11030-022-10384-x PubMed DOI

Shen N., Wang T., Gan Q., Liu S., Wang L., Jin B. (2022). Plant flavonoids: Classification, distribution, biosynthesis, and antioxidant activity. Food Chem. 383, 132531. 10.1016/j.foodchem.2022.132531 PubMed DOI

Shike M., Doane A. S., Russo L., Cabal R., Reis-Filho J. S., Gerald W., et al. (2014). The effects of soy supplementation on gene expression in breast cancer: A randomized placebo-controlled study. J. Natl. Cancer Inst. 106, dju189. 10.1093/jnci/dju189 PubMed DOI PMC

Sridharan S., Howard C. M., Tilley A. M. C., Subramaniyan B., Tiwari A. K., Ruch R. J., et al. (2019). Novel and alternative targets against breast cancer stemness to combat chemoresistance. Frontiers in Oncology [Internet]. 2019 [cited 2023 Feb 2];9. Available from: https://www.frontiersin.org/articles/10.3389/fonc.2019.01003 . PubMed DOI PMC

Stendell-Hollis N. R., Thomson C. A., Thompson P. A., Bea J. W., Cussler E. C., Hakim I. A. (2010). Green tea improves metabolic biomarkers, not weight or body composition: A pilot study in overweight breast cancer survivors. J. Hum. Nutr. Diet. 23, 590–600. 10.1111/j.1365-277X.2010.01078.x PubMed DOI PMC

Sung H., Ferlay J., Siegel R. L., Laversanne M., Soerjomataram I., Jemal A., et al. (2021). Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA A Cancer J. Clin. 71, 209–249. 10.3322/caac.21660 PubMed DOI

Teshome N., Degu A., Ashenafi E., Ayele E., Abebe A. (2022). Evaluation of wound healing and anti-inflammatory activity of hydroalcoholic leaf extract of Clematis simensis fresen (ranunculaceae). Clin. Cosmet. Investig. Dermatol 15, 1883–1897. 10.2147/CCID.S384419 PubMed DOI PMC

Thilakarathna S. H., Rupasinghe H. P. V. (2013). Flavonoid bioavailability and attempts for bioavailability enhancement. Nutrients 5, 3367–3387. 10.3390/nu5093367 PubMed DOI PMC

Truong V. N-P., Nguyen Y. T-K., Cho S-K. (2021). Ampelopsin suppresses stem cell properties accompanied by attenuation of oxidative phosphorylation in chemo- and radio-resistant MDA-MB-231 breast cancer cells. Pharm. (Basel) 14, 794. 10.3390/ph14080794 PubMed DOI PMC

Tsai K-J., Tsai H-Y., Tsai C-C., Chen T-Y., Hsieh T-H., Chen C-L., et al. (2021). Luteolin inhibits breast cancer stemness and enhances chemosensitivity through the nrf2-mediated pathway. Molecules 26, 6452. 10.3390/molecules26216452 PubMed DOI PMC

Tuasha N., Escobar Z., Seifu D., Gadisa E., Petros B., Sterner O., et al. (2022). Cytotoxic and other bioactivities of a novel and known sesquiterpene lactones isolated from Vernonia leopoldi (Sch. Bip. ex Walp.) Vatke in breast cancer cell lines. Toxicol. Rep. 9, 382–392. 10.1016/j.toxrep.2022.02.011 PubMed DOI PMC

Tuasha N., Seifu D., Gadisa E., Petros B., Oredsson S. (2020). Solvent fractions of selected Ethiopian medicinal plants used in traditional breast cancer treatment inhibit cancer stem cells in a breast cancer cell line. BMC Complement. Med. Ther. 20, 366. 10.1186/s12906-020-03154-5 PubMed DOI PMC

Tuli H. S., Tuorkey M. J., Thakral F., Sak K., Kumar M., Sharma A. K., et al. (2019). Molecular mechanisms of action of genistein in cancer: Recent advances. Front. Pharmacol. 10, 1336. 10.3389/fphar.2019.01336 PubMed DOI PMC

Tuyen P. T., Xuan T. D., Khang D. T., Ahmad A., Quan N. V., Tu Anh T. T., et al. (2017). Phenolic Compositions and Antioxidant Properties in Bark, Flower, Inner Skin, Kernel and Leaf Extracts of Castanea crenata Sieb. et Zucc. Zucc. Antioxidants (Basel) 6, 31. 10.3390/antiox6020031 PubMed DOI PMC

Vaz-Luis I., Lin N. U., Keating N. L., Barry W. T., Winer E. P., Freedman R. A. (2017). Factors associated with early mortality among patients with de novo metastatic breast cancer: A population-based study. Oncologist 22, 386–393. 10.1634/theoncologist.2016-0369 PubMed DOI PMC

Voon F-L., Sulaiman M. R., Akhtar M. N., Idris M. F., Akira A., Perimal E. K., et al. (2017). Cardamonin (2′,4′-dihydroxy-6′-methoxychalcone) isolated from Boesenbergia rotunda (L.) Mansf. inhibits CFA-induced rheumatoid arthritis in rats. Eur. J. Pharmacol. 794, 127–134. 10.1016/j.ejphar.2016.11.009 PubMed DOI

Wang L., Lee I-M., Zhang S. M., Blumberg J. B., Buring J. E., Sesso H. D. (2009). Dietary intake of selected flavonols, flavones, and flavonoid-rich foods and risk of cancer in middle-aged and older women. Am. J. Clin. Nutr. 89, 905–912. 10.3945/ajcn.2008.26913 PubMed DOI PMC

Wang M., Wang Y., Zhong J. (2015). Side population cells and drug resistance in breast cancer. Mol. Med. Rep. 11, 4297–4302. 10.3892/mmr.2015.3291 PubMed DOI

Wang R., Yang L., Li S., Ye D., Yang L., Liu Q., et al. (2018). Quercetin inhibits breast cancer stem cells via downregulation of aldehyde dehydrogenase 1A1 (ALDH1A1), chemokine receptor type 4 (CXCR4), mucin 1 (MUC1), and epithelial cell adhesion molecule (EpCAM). Med. Sci. Monit. 24, 412–420. 10.12659/msm.908022 PubMed DOI PMC

Wang Y., Li W., Patel S. S., Cong J., Zhang N., Sabbatino F., et al. (2014). Blocking the formation of radiation-induced breast cancer stem cells. Oncotarget 5, 3743–3755. 10.18632/oncotarget.1992 PubMed DOI PMC

Weng L., Zhang H., Li X., Zhan H., Chen F., Han L., et al. (2017). Ampelopsin attenuates lipopolysaccharide-induced inflammatory response through the inhibition of the NF-κB and JAK2/STAT3 signaling pathways in microglia. Int. Immunopharmacol. 44, 1–8. 10.1016/j.intimp.2016.12.018 PubMed DOI

Woo Y., Oh J., Kim J-S. (2017). Suppression of Nrf2 activity by chestnut leaf extract increases chemosensitivity of breast cancer stem cells to paclitaxel. Nutrients 9, 760. 10.3390/nu9070760 PubMed DOI PMC

Wu T., Harder B. G., Wong P. K., Lang J. E., Zhang D. D. (2015). Oxidative stress, mammospheres and Nrf2-new implication for breast cancer therapy? Mol. Carcinog. 54, 1494–1502. 10.1002/mc.22202 PubMed DOI PMC

Yousefnia S., Ghaedi K., Seyed Forootan F., Nasr Esfahani M. H. (2019). Characterization of the stemness potency of mammospheres isolated from the breast cancer cell lines. Tumour Biol. 41, 1010428319869101. 10.1177/1010428319869101 PubMed DOI

Yousefnia S., Naseri D., Seyed Forootan F., Tabatabaeian M., Moattar F., Ghafghazi T., et al. (2020). Suppressive role of Viola odorata extract on malignant characters of mammosphere-derived breast cancer stem cells. Clin. Transl. Oncol. 22, 1619–1634. 10.1007/s12094-020-02307-9 PubMed DOI

Yu F., Li J., Chen H., Fu J., Ray S., Huang S., et al. (2011). Kruppel-like factor 4 (KLF4) is required for maintenance of breast cancer stem cells and for cell migration and invasion. Oncogene 30, 2161–2172. 10.1038/onc.2010.591 PubMed DOI PMC

Zhang C., Samanta D., Lu H., Bullen J. W., Zhang H., Chen I., et al. (2016). Hypoxia induces the breast cancer stem cell phenotype by HIF-dependent and ALKBH5-mediated m6A-demethylation of NANOG mRNA. Proc. Natl. Acad. Sci. U. S. A. 113, E2047–E2056. 10.1073/pnas.1602883113 PubMed DOI PMC

Zhang G., Wang Y., Zhang Y., Wan X., Li J., Liu K., et al. (2012). Anti-cancer activities of tea epigallocatechin-3-gallate in breast cancer patients under radiotherapy. Curr. Mol. Med. 12, 163–176. 10.2174/156652412798889063 PubMed DOI PMC

Zhang X., Powell K., Li L. (2020). Breast cancer stem cells: Biomarkers, identification and isolation methods, regulating mechanisms, cellular origin, and beyond. Cancers (Basel) 12, 3765. 10.3390/cancers12123765 PubMed DOI PMC

Zhao J., Yang J., Xie Y. (2019). Improvement strategies for the oral bioavailability of poorly water-soluble flavonoids: An overview. Int. J. Pharm. 570, 118642. 10.1016/j.ijpharm.2019.118642 PubMed DOI

Zhou Y., Shu F., Liang X., Chang H., Shi L., Peng X., et al. (2014). Ampelopsin induces cell growth inhibition and apoptosis in breast cancer cells through ROS generation and endoplasmic reticulum stress pathway. PLoS One 9, e89021. 10.1371/journal.pone.0089021 PubMed DOI PMC

Zhu W., Jia L., Chen G., Zhao H., Sun X., Meng X., et al. (2016). Epigallocatechin-3-gallate ameliorates radiation-induced acute skin damage in breast cancer patients undergoing adjuvant radiotherapy. Oncotarget 7, 48607–48613. 10.18632/oncotarget.9495 PubMed DOI PMC