BACKGROUND: Cancer remains a major global health challenge, necessitating innovative prevention and treatment approaches. Certain plants, adapted to specific environments, may exhibit bioactive properties with potential anticancer applications. HYPOTHESIS: Seaberry (Hippophae rhamnoides L.) fruit peels may exert anticancer effects in breast carcinoma (BC) models through the additive or synergistic actions of their unique secondary metabolites. METHODS: H. rhamnoides fruit peel extracts were analyzed using the LC-DAD-MS and LC-DAD techniques to profile the content of carotenoids and flavonoids, respectively. The preclinical study evaluated seaberry fruit peel extracts in BC models: (1) a syngeneic 4T1 mouse breast adenocarcinoma model (triple-negative), (2) a rat model of chemically induced mammary carcinogenesis, and (3) in vitro studies with MCF-7 (hormone receptor-positive) and MDA-MB-231 (triple-negative) BC cell lines. RESULTS: LC-DAD-MS and LC-DAD analyses identified dominant metabolites, including isorhamnetin, quercetin glycosides, kaempferol glycosides, catechin, zeaxanthin, and lutein. In the 4T1 mouse model, seaberry treatment resulted in a significant, dose-dependent reduction in tumor volume (43% and 48% compared to controls) and a decrease in the mitotic activity index. Serum cytokine analysis showed dose-dependent reductions in IL-6, IL-10, and TNF-α. In the rat chemopreventive model, high-dose seaberry improved cancer prognosis by reducing the ratio of poorly differentiated tumors and increasing caspase-3 and Bax expression while decreasing Ki-67 and malondialdehyde levels. Both treatment doses elevated the Bax/Bcl-2 ratio and reduced the expression of cancer stem cell markers CD44, EpCam, and VEGF compared to controls. Epigenetic analyses revealed histone modifications (H4K16ac, H4K20me3) and altered methylation of tumor-suppressor genes (PITX2, RASSF1, PTEN, TIMP3). Microarray analysis (758 miRNAs) identified beneficial changes in nine oncogenic/tumor-suppressive miRNAs, including miR-10a-5p, miR-322-5p, miR-450a-5p, miR-142-5p, miR-148b-3p, miR-1839-3p, miR-18a-5p, miR-1949, and miR-347. In vitro, ethanolic seaberry extract conferred partial resistance to cisplatin-induced cytotoxicity in MCF-7 and MDA-MB-231 cells at IC50 concentrations. CONCLUSION: This study of H. rhamnoides in rodent BC models shows promising data but requires rigorous, long-term validation. Integrating plant-based nutraceuticals into oncology necessitates precise cancer-type profiling and patient stratification for effective personalized treatments.

Biobank for Cancer and Rare Diseases Jessenius Faculty of Medicine Comenius University in Bratislava Martin Slovakia

Biomedical Centre Martin Jessenius Faculty of Medicine Comenius University in Bratislava Martin Slovakia

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 Animal Physiology Institute of Biology and Ecology Faculty of Science P J Safarik University Kosice Slovakia

Department of Botany Institute of Biology and Ecology Faculty of Science P J Safarik University Kosice Slovakia

Department of Microbiology and Immunology Jessenius Faculty of Medicine Comenius University in Bratislava Martin Slovakia

Department of Molecular Pharmacy Faculty of Pharmacy Masaryk University Brno Czechia

Department of Natural Drugs Faculty of Pharmacy Masaryk University Brno Czechia

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

Department of Pathology St Elisabeth Oncology Institute Bratislava Slovakia

Department of Pharmacology Faculty of Medicine P J Šafárik University Košice Slovakia

Laboratory of Experimental and Clinical Regenerative Medicine Small Animal Clinic University of Veterinary Medicine and Pharmacy Kosice Slovakia

Small Animal Clinic University of Veterinary Medicine and Pharmacy Kosice Slovakia

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Aanniz T., Bouyahya A., Balahbib A., El Kadri K., Khalid A., Makeen H. A., et al. (2024). Natural bioactive compounds targeting DNA methyltransferase enzymes in cancer: mechanisms insights and efficiencies. Chemico-Biological Interact. 392, 110907. 10.1016/j.cbi.2024.110907 PubMed DOI

Abadi A. J., Mirzaei S., Mahabady M. K., Hashemi F., Zabolian A., Hashemi F., et al. (2022). Curcumin and its derivatives in cancer therapy: potentiating antitumor activity of cisplatin and reducing side effects. Phytother. Res. 36, 189–213. 10.1002/ptr.7305 PubMed DOI

Abotaleb M., Samuel S. M., Varghese E., Varghese S., Kubatka P., Liskova A., et al. (2018). Flavonoids in cancer and apoptosis. Cancers (Basel) 11, 28. 10.3390/cancers11010028 PubMed DOI PMC

Açar Y., Akbulut G. (2023). Nutritional epigenetics and phytochemicals in cancer formation. J. Am. Nutr. Assoc. 42, 700–705. 10.1080/27697061.2022.2147106 PubMed DOI

Adams L. S., Zhang Y., Seeram N. P., Heber D., Chen S. (2010). Pomegranate ellagitannin-derived compounds exhibit antiproliferative and antiaromatase activity in breast cancer cells in vitro . Cancer Prev. Res. (Phila) 3, 108–113. 10.1158/1940-6207.CAPR-08-0225 PubMed DOI PMC

Alateyah N., Alsafran M., Usman K., Ouhtit A. (2023). Molecular evidence of breast cancer cell proliferation inhibition by a combination of selected Qatari medicinal plants crude extracts. Nutrients 15, 4276. 10.3390/nu15194276 PubMed DOI PMC

Arun R. P., Cahill H. F., Marcato P. (2022). Breast cancer subtype-specific miRNAs: networks, impacts, and the potential for intervention. Biomedicines 10, 651. 10.3390/biomedicines10030651 PubMed DOI PMC

Banerjee S., Nau S., Hochwald S. N., Xie H., Zhang J. (2023). Anticancer properties and mechanisms of botanical derivatives. Phytomed. Plus 3, 100396. 10.1016/j.phyplu.2022.100396 DOI

Batbold U., Liu J.-J. (2022). Chemosensitization effect of seabuckthorn (Hippophae rhamnoides L.) pulp oil via autophagy and senescence in NSCLC cells. Foods 11, 1517. 10.3390/foods11101517 PubMed DOI PMC

Bieg D., Sypniewski D., Nowak E., Bednarek I. (2019). MiR-424-3p suppresses galectin-3 expression and sensitizes ovarian cancer cells to cisplatin. Arch. Gynecol. Obstet. 299, 1077–1087. 10.1007/s00404-018-4999-7 PubMed DOI PMC

Bishayee A., Mandal A., Bhattacharyya P., Bhatia D. (2016). Pomegranate exerts chemoprevention of experimentally induced mammary tumorigenesis by suppression of cell proliferation and induction of apoptosis. Nutr. Cancer 68, 120–130. 10.1080/01635581.2016.1115094 PubMed DOI PMC

Campbell T. M., Campbell E. K., Culakova E., Blanchard L. M., Wixom N., Guido J. J., et al. (2024). A whole-food, plant-based randomized controlled trial in metastatic breast cancer: weight, cardiometabolic, and hormonal outcomes. Breast Cancer Res. Treat. 205, 257–266. 10.1007/s10549-024-07266-1 PubMed DOI PMC

Chan M. M., Chen R., Fong D. (2018). Targeting cancer stem cells with dietary phytochemical - repositioned drug combinations. Cancer Lett. 433, 53–64. 10.1016/j.canlet.2018.06.034 PubMed DOI PMC

Chatterjee B., Ghosh K., Kanade S. R. (2019). Resveratrol modulates epigenetic regulators of promoter histone methylation and acetylation that restores BRCA1, p53, p21CIP1 in human breast cancer cell lines. Biofactors 45, 818–829. 10.1002/biof.1544 PubMed DOI

Chen Z.-H., Chen Y.-B., Yue H.-R., Zhou X.-J., Ma H.-Y., Wang X., et al. (2023). PAX5-miR-142 feedback loop promotes breast cancer proliferation by regulating DNMT1 and ZEB1. Mol. Med. 29, 89. 10.1186/s10020-023-00681-y PubMed DOI PMC

Choudhari A. S., Mandave P. C., Deshpande M., Ranjekar P., Prakash O. (2020). Phytochemicals in cancer treatment: from preclinical studies to clinical practice. Front. Pharmacol. 10, 1614. 10.3389/fphar.2019.01614 PubMed DOI PMC

Cortes J., Perez-Garcia J., Levy C., Gómez Pardo P., Bourgeois H., Spazzapan S., et al. (2018). Open-label randomised phase III trial of vinflunine versus an alkylating agent in patients with heavily pretreated metastatic breast cancer. Ann. Oncol. 29, 881–887. 10.1093/annonc/mdy051 PubMed DOI

Crew K. D., Brown P., Greenlee H., Bevers T. B., Arun B., Hudis C., et al. (2012). Phase IB randomized, double-blinded, placebo-controlled, dose escalation study of polyphenon E in women with hormone receptor-negative breast cancer. Cancer Prev. Res. (Phila) 5, 1144–1154. 10.1158/1940-6207.CAPR-12-0117 PubMed DOI PMC

Dai W., He J., Zheng L., Bi M., Hu F., Chen M., et al. (2019). miR-148b-3p, miR-190b, and miR-429 regulate cell progression and act as potential biomarkers for breast cancer. J. Breast Cancer 22, 219–236. 10.4048/jbc.2019.22.e19 PubMed DOI PMC

Dandawate P. R., Subramaniam D., Jensen R. A., Anant S. (2016). Targeting cancer stem cells and signaling pathways by phytochemicals: novel approach for breast cancer therapy. Semin. Cancer Biol. 40 (41), 192–208. 10.1016/j.semcancer.2016.09.001 PubMed DOI PMC

Debnath T., Nath N. C. D., Kim E.-K., Lee K.-G. (2017). Role of phytochemicals in the modulation of miRNA expression in cancer. Food Funct. 8, 3432–3442. 10.1039/C7FO00739F PubMed DOI

Dehnavi M. K., Ebrahimpour-Koujan S., Lotfi K., Azadbakht L. (2024). The association between circulating carotenoids and risk of breast cancer: a systematic review and dose–response meta-analysis of prospective studies. Adv. Nutr. 15, 100135. 10.1016/j.advnut.2023.10.007 PubMed DOI PMC

Demečková V., Solár P., Hrčková G., Mudroňová D., Bojková B., Kassayová M., et al. (2017). Immodin and its immune system supportive role in paclitaxel therapy of 4T1 mouse breast cancer. Biomed. Pharmacother. 89, 245–256. 10.1016/j.biopha.2017.02.034 PubMed DOI

Di Napoli R., Balzano N., Mascolo A., Cimmino C., Vitiello A., Zovi A., et al. (2023). What is the role of nutraceutical products in cancer patients? A systematic review of randomized clinical trials. Nutrients 15, 3249. 10.3390/nu15143249 PubMed DOI PMC

Sea Buckthorn Uses, Benefits & Dosage (n.d.). Drugs. Com. Available online at: https://www.drugs.com/npp/sea-buckthorn.html (Accessed April 1, 2025).

Dubey R. K., Shukla S., Shukla V., Singh S. (2023). Sea buckthorn: a potential dietary supplement with multifaceted therapeutic activities. Intell. Pharm. 2, 681–687. 10.1016/j.ipha.2023.12.003 DOI

Duo J., Ying G.-G., Wang G.-W., Zhang L. (2012). Quercetin inhibits human breast cancer cell proliferation and induces apoptosis via Bcl-2 and Bax regulation. Mol. Med. Rep. 5, 1453–1456. 10.3892/mmr.2012.845 PubMed DOI

Dvorska D., Mazurakova A., Lackova L., Šebová D., Kajo K., Samec M., et al. (2024). Aronia melanocarpa L. fruit peels show anti-cancer effects in preclinical models of breast carcinoma: the perspectives in the chemoprevention and therapy modulation. Front. Oncol. 14, 1463656. 10.3389/fonc.2024.1463656 PubMed DOI PMC

El Omari N., Bakrim S., Bakha M., Lorenzo J. M., Rebezov M., Shariati M. A., et al. (2021). Natural bioactive compounds targeting epigenetic pathways in cancer: a review on alkaloids, terpenoids, quinones, and isothiocyanates. Nutrients 13, 3714. 10.3390/nu13113714 PubMed DOI PMC

Feng X., Song Z., Tao A., Gong P., Pei W., Zong R. (2023). Prediction of active marker of seabuckthorn polysaccharides for prevention and treatment of cervical cancer and mechanism study. Front. Nutr. 10, 1136590. 10.3389/fnut.2023.1136590 PubMed DOI PMC

Gao Y., Tollefsbol T. O. (2018). Combinational proanthocyanidins and resveratrol synergistically inhibit human breast cancer cells and impact epigenetic−mediating machinery. Int. J. Mol. Sci. 19, 2204. 10.3390/ijms19082204 PubMed DOI PMC

Gong X., Smith J. R., Swanson H. M., Rubin L. P. (2018). Carotenoid lutein selectively inhibits breast cancer cell growth and potentiates the effect of chemotherapeutic agents through ROS-mediated mechanisms. Molecules 23, 905. 10.3390/molecules23040905 PubMed DOI PMC

Grasselly C., Denis M., Bourguignon A., Talhi N., Mathe D., Tourette A., et al. (2018). The antitumor activity of combinations of cytotoxic chemotherapy and immune checkpoint inhibitors is model-dependent. Front. Immunol. 9, 2100. 10.3389/fimmu.2018.02100 PubMed DOI PMC

Grey C., Widén C., Adlercreutz P., Rumpunen K., Duan R.-D. (2010). Antiproliferative effects of sea buckthorn (Hippophae rhamnoides L.) extracts on human colon and liver cancer cell lines. Food Chem. 120, 1004–1010. 10.1016/j.foodchem.2009.11.039 DOI

Hackam D. G., Redelmeier D. A. (2006). Translation of research evidence from animals to humans. JAMA 296, 1731–1732. 10.1001/jama.296.14.1731 PubMed DOI

Hao C., Sheng Z., Wang W., Feng R., Zheng Y., Xiao Q., et al. (2023). Tumor-derived exosomal miR-148b-3p mediates M2 macrophage polarization via TSC2/mTORC1 to promote breast cancer migration and invasion. Thorac. Cancer 14, 1477–1491. 10.1111/1759-7714.14891 PubMed DOI PMC

Hu S., Huang L., Meng L., Sun H., Zhang W., Xu Y. (2015). Isorhamnetin inhibits cell proliferation and induces apoptosis in breast cancer via Akt and mitogen-activated protein kinase kinase signaling pathways. Mol. Med. Rep. 12, 6745–6751. 10.3892/mmr.2015.4269 PubMed DOI PMC

Huang T., Song X., Xu D., Tiek D., Goenka A., Wu B., et al. (2020). Stem cell programs in cancer initiation, progression, and therapy resistance. Theranostics 10, 8721–8743. 10.7150/thno.41648 PubMed DOI PMC

Jabeen A., Sharma A., Gupta I., Kheraldine H., Vranic S., Al Moustafa A.-E., et al. (2020). Elaeagnus angustifolia plant extract inhibits epithelial-mesenchymal transition and induces apoptosis via HER2 inactivation and JNK pathway in HER2-positive breast cancer cells. Molecules 25, 4240. 10.3390/molecules25184240 PubMed DOI PMC

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

Jaśniewska A., Diowksz A. (2021). Wide spectrum of active compounds in sea buckthorn (Hippophae rhamnoides) for disease prevention and food production. Antioxidants (Basel) 10, 1279. 10.3390/antiox10081279 PubMed DOI PMC

Jeyabalan J., Aqil F., Munagala R., Annamalai L., Vadhanam M. V., Gupta R. C. (2014). Chemopreventive and therapeutic activity of dietary blueberry against estrogen-mediated breast cancer. J. Agric. Food Chem. 62, 3963–3971. 10.1021/jf403734j PubMed DOI PMC

Ji M., Gong X., Li X., Wang C., Li M. (2020). Advanced research on the antioxidant activity and mechanism of polyphenols from Hippophae species-A review. Molecules 25, 917. 10.3390/molecules25040917 PubMed DOI PMC

Jiang F., Li Y., Mu J., Hu C., Zhou M., Wang X., et al. (2016). Glabridin inhibits cancer stem cell-like properties of human breast cancer cells: an epigenetic regulation of miR-148a/SMAd2 signaling. Mol. Carcinog. 55, 929–940. 10.1002/mc.22333 PubMed DOI

Juan C. A., Pérez de la Lastra J. M., Plou F. J., Pérez-Lebeña E. (2021). The chemistry of reactive oxygen species (ROS) revisited: outlining their role in biological macromolecules (DNA, lipids and proteins) and induced pathologies. Int. J. Mol. Sci. 22, 4642. 10.3390/ijms22094642 PubMed DOI PMC

Kang H. J., Lee S. H., Price J. E., Kim L. S. (2009). Curcumin suppresses the paclitaxel-induced nuclear factor-kappaB in breast cancer cells and potentiates the growth inhibitory effect of paclitaxel in a breast cancer nude mice model. Breast J. 15, 223–229. 10.1111/j.1524-4741.2009.00709.x PubMed DOI

Kapinova A., Stefanicka P., Kubatka P., Zubor P., Uramova S., Kello M., et al. (2017a). 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

Kapinova A., Stefanicka P., Kubatka P., Zubor P., Uramova S., Kello M., et al. (2017b). 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

Ke K., Lou T. (2017). MicroRNA-10a suppresses breast cancer progression via PI3K/Akt/mTOR pathway. Oncol. Lett. 14, 5994–6000. 10.3892/ol.2017.6930 PubMed DOI PMC

Khan A., Khan A., Khan M. A., Malik Z., Massey S., Parveen R., et al. (2024). Phytocompounds targeting epigenetic modulations: an assessment in cancer. Front. Pharmacol. 14, 1273993. 10.3389/fphar.2023.1273993 PubMed DOI PMC

Khan S., Wall D., Curran C., Newell J., Kerin M. J., Dwyer R. M. (2015). MicroRNA-10a is reduced in breast cancer and regulated in part through retinoic acid. BMC Cancer 15, 345. 10.1186/s12885-015-1374-y PubMed DOI PMC

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

Kolenda T., Guglas K., Kopczyńska M., Sobocińska J., Teresiak A., Bliźniak R., et al. (2020). Good or not good: role of miR-18a in cancer biology. Rep. Pract. Oncol. Radiother. 25, 808–819. 10.1016/j.rpor.2020.07.006 PubMed DOI PMC

Kubatka P., Kapinová A., Kello M., Kruzliak P., Kajo K., Výbohová D., et al. (2016a). 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., Kruzliak P., Výbohová D., Mojžiš J., et al. (2017a). Oregano demonstrates distinct tumour-suppressive effects in the breast carcinoma model. Eur. J. Nutr. 56, 1303–1316. 10.1007/s00394-016-1181-5 PubMed DOI

Kubatka P., Kello M., Kajo K., Kruzliak P., Výbohová D., Šmejkal K., et al. (2016b). Young barley indicates antitumor effects in experimental breast cancer in vivo and in vitro . Nutr. Cancer 68, 611–621. 10.1080/01635581.2016.1154577 PubMed DOI

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

Kubatka P., Kello M., Kajo K., Samec M., Liskova A., Jasek K., et al. (2020b). 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., Koklesova L., Kuruc T., Samec M., Kajo K., et al. (2024). Salvia officinalis L. exerts oncostatic effects in rodent and in vitro models of breast carcinoma. Front. Pharmacol. 15, 1216199. 10.3389/fphar.2024.1216199 PubMed DOI PMC

Kubatka P., Uramova S., Kello M., Kajo K., Kruzliak P., Mojzis J., et al. (2017b). 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

Kubatka P., Uramova S., Kello M., Kajo K., Samec M., Jasek K., et al. (2019). Anticancer activities of Thymus vulgaris L. In experimental breast carcinoma in vivo and in vitro . Int. J. Mol. Sci. 20, 1749. 10.3390/ijms20071749 PubMed DOI PMC

Lewis K. A., Jordan H. R., Tollefsbol T. O. (2018). Effects of SAHA and EGCG on growth potentiation of triple-negative breast cancer cells. Cancers (Basel) 11, 23. 10.3390/cancers11010023 PubMed DOI PMC

Li Y., Meeran S. M., Patel S. N., Chen H., Hardy T. M., Tollefsbol T. O. (2013). Epigenetic reactivation of estrogen receptor-α (ERα) by genistein enhances hormonal therapy sensitivity in ERα-negative breast cancer. Mol. Cancer 12, 9. 10.1186/1476-4598-12-9 PubMed DOI PMC

Liao W., Zhang L., Chen X., Xiang J., Zheng Q., Chen N., et al. (2023). Targeting cancer stem cells and signalling pathways through phytochemicals: a promising approach against colorectal cancer. Phytomedicine 108, 154524. 10.1016/j.phymed.2022.154524 PubMed DOI

Liskova A., Kubatka P., Samec M., Zubor P., Mlyncek M., Bielik T., et al. (2019a). Dietary phytochemicals targeting cancer stem cells. Molecules 24, 899. 10.3390/molecules24050899 PubMed DOI PMC

Liskova A., Kubatka P., Samec M., Zubor P., Mlyncek M., Bielik T., et al. (2019b). Dietary phytochemicals targeting cancer stem cells. Molecules 24, 899. 10.3390/molecules24050899 PubMed DOI PMC

Liu Y., Yang H. (2023). MiR-18a-5p attenuates HER2-positive breast cancer development by regulating PI3K/AKT pathway. Cancer Biol. Ther. 24, 2224512. 10.1080/15384047.2023.2224512 PubMed DOI PMC

Liu Z.-L., Chen H.-H., Zheng L.-L., Sun L.-P., Shi L. (2023). Angiogenic signaling pathways and anti-angiogenic therapy for cancer. Sig Transduct. Target Ther. 8, 198–239. 10.1038/s41392-023-01460-1 PubMed DOI PMC

Ma X., Zhang X., Wang X., Wang C., Ma Y. (2023). The role of kaempferol in gynaecological malignancies: progress and perspectives. Front. Pharmacol. 14, 1310416. 10.3389/fphar.2023.1310416 PubMed DOI PMC

Marino P., Mininni M., Deiana G., Marino G., Divella R., Bochicchio I., et al. (2024). Healthy lifestyle and cancer risk: modifiable risk factors to prevent cancer. Nutrients 16, 800. 10.3390/nu16060800 PubMed DOI PMC

Masoodi K. Z., Wani W., Dar Z. A., Mansoor S., Anam-ul-Haq S., Farooq I., et al. (2020). Sea buckthorn (Hippophae rhamnoides L.) inhibits cellular proliferation, wound healing and decreases expression of prostate specific antigen in prostate cancer cells in vitro . J. Funct. Foods 73, 104102. 10.1016/j.jff.2020.104102 DOI

Maugeri A., Calderaro A., Patanè G. T., Navarra M., Barreca D., Cirmi S., et al. (2023). Targets involved in the anti-cancer activity of quercetin in breast, colorectal and liver neoplasms. Int. J. Mol. Sci. 24, 2952. 10.3390/ijms24032952 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

Meng J., Guo F., Xu H., Liang W., Wang C., Yang X.-D. (2016). Combination therapy using Co-encapsulated resveratrol and paclitaxel in liposomes for drug resistance reversal in breast cancer cells in vivo . Sci. Rep. 6, 22390. 10.1038/srep22390 PubMed DOI PMC

Mihal M., Roychoudhury S., Sirotkin A. V., Kolesarova A. (2023). Sea buckthorn, its bioactive constituents, and mechanism of action: potential application in female reproduction. Front. Endocrinol. 14, 1244300. 10.3389/fendo.2023.1244300 PubMed DOI PMC

Nagy S., Petrosky S. N., Demory Beckler M., Kesselman M. M. (n.d.). The impact of modern dietary practices on cancer risk and progression: a systematic review. Cureus 15, e46639. 10.7759/cureus.46639 PubMed DOI PMC

Nair M. G., Mavatkar A. D., Naidu C. M., V. P. S., C. E. A., Rajarajan S., et al. (2024). Elucidating the role of MicroRNA-18a in propelling a hybrid epithelial–mesenchymal phenotype and driving malignant progression in ER-negative breast cancer. Cells, 13, 821. 10.3390/cells13100821 PubMed DOI PMC

Nazeri M., Mirzaie-asl A., Saidijam M., Moradi M. (2020). Methanolic extract of Artemisia absinthium prompts apoptosis, enhancing expression of Bax/Bcl-2 ratio, cell cycle arrest, caspase-3 activation and mitochondrial membrane potential destruction in human colorectal cancer HCT-116 cells. Mol. Biol. Rep. 47, 8831–8840. 10.1007/s11033-020-05933-2 PubMed DOI

Ng J. M.-K., Yu J. (2015). Promoter hypermethylation of tumour suppressor genes as potential biomarkers in colorectal cancer. Int. J. Mol. Sci. 16, 2472–2496. 10.3390/ijms16022472 PubMed DOI PMC

Nguyen L. T., Lee Y.-H., Sharma A. R., Park J.-B., Jagga S., Sharma G., et al. (2017). Quercetin induces apoptosis and cell cycle arrest in triple-negative breast cancer cells through modulation of Foxo3a activity. Korean J. Physiol. Pharmacol. 21, 205–213. 10.4196/kjpp.2017.21.2.205 PubMed DOI PMC

Nirgude S., Desai S., Choudhary B. (2022). Genome-wide differential DNA methylation analysis of MDA-MB-231 breast cancer cells treated with curcumin derivatives, ST08 and ST09. BMC Genomics 23, 807. 10.1186/s12864-022-09041-2 PubMed DOI PMC

Nishimuta H., Nakagawa T., Nomura N., Yabuki M. (2013). Species differences in hepatic and intestinal metabolic activities for 43 human cytochrome P450 substrates between humans and rats or dogs. Xenobiotica 43, 948–955. 10.3109/00498254.2013.787155 PubMed DOI

Nishiyama A., Nakanishi M. (2021). Navigating the DNA methylation landscape of cancer. Trends Genet. 37, 1012–1027. 10.1016/j.tig.2021.05.002 PubMed DOI

Oh J., Hlatky L., Jeong Y.-S., Kim D. (2016). Therapeutic effectiveness of anticancer phytochemicals on cancer stem cells. Toxins 8, 199. 10.3390/toxins8070199 PubMed DOI PMC

Olas B., Skalski B., Ulanowska K. (2018a). The anticancer activity of sea Buckthorn [Elaeagnus rhamnoides (L.) A. Nelson]. Front. Pharmacol. 9, 232. 10.3389/fphar.2018.00232 PubMed DOI PMC

Olas B., Skalski B., Ulanowska K. (2018b). The anticancer activity of sea Buckthorn [Elaeagnus rhamnoides (L.) A. Nelson]. Front. Pharmacol. 9, 232. 10.3389/fphar.2018.00232 PubMed DOI PMC

Ouhtit A., Gaur R. L., Abdraboh M., Ireland S. K., Rao P. N., Raj S. G., et al. (2013). Simultaneous inhibition of cell-cycle, proliferation, survival, metastatic pathways and induction of apoptosis in breast cancer cells by a phytochemical super-cocktail: genes that underpin its mode of action. J. Cancer 4, 703–715. 10.7150/jca.7235 PubMed DOI PMC

Pal M. K., Jaiswar S. P., Srivastav A. K., Goyal S., Dwivedi A., Verma A., et al. (2016). Synergistic effect of piperine and paclitaxel on cell fate via cyt-c, Bax/Bcl-2-caspase-3 pathway in ovarian adenocarcinomas SKOV-3 cells. Eur. J. Pharmacol. 791, 751–762. 10.1016/j.ejphar.2016.10.019 PubMed DOI

Parveen A., Subedi L., Kim H. W., Khan Z., Zahra Z., Farooqi M. Q., et al. (2019). Phytochemicals targeting VEGF and VEGF-related multifactors as anticancer therapy. J. Clin. Med. 8, 350. 10.3390/jcm8030350 PubMed DOI PMC

Paul J. K., Azmal M., Haque A. S. N. B., Talukder O. F., Meem M., Ghosh A. (2024). Phytochemical-mediated modulation of signaling pathways: a promising avenue for drug discovery. Adv. Redox Res. 13, 100113. 10.1016/j.arres.2024.100113 DOI

Pop R. M., Weesepoel Y., Socaciu C., Pintea A., Vincken J.-P., Gruppen H. (2014). Carotenoid composition of berries and leaves from six Romanian sea Buckthorn (Hippophae rhamnoides L.) varieties. Food Chem. 147, 1–9. 10.1016/j.foodchem.2013.09.083 PubMed DOI

Prajapati K. S., Gupta S., Kumar S. (2022). Targeting breast cancer-derived stem cells by dietary phytochemicals: a strategy for cancer prevention and treatment. Cancers (Basel) 14, 2864. 10.3390/cancers14122864 PubMed DOI PMC

Qin W., Zhang K., Clarke K., Weiland T., Sauter E. R. (2014). Methylation and miRNA effects of resveratrol on mammary tumors vs. normal tissue. Nutr. Cancer 66, 270–277. 10.1080/01635581.2014.868910 PubMed DOI

Qin W., Zhu W., Shi H., Hewett J. E., Ruhlen R. L., MacDonald R. S., et al. (2009). Soy isoflavones have an antiestrogenic effect and alter mammary promoter hypermethylation in healthy premenopausal women. Nutr. Cancer 61, 238–244. 10.1080/01635580802404196 PubMed DOI PMC

Rabinovich I., Sebastião A. P. M, Lima R. S., Urban C. A., Junior E. S., Anselmi K. F., et al. (2018). Cancer stem cell markers ALDH1 and CD44+/CD24- phenotype and their prognosis impact in invasive ductal carcinoma. Eur J Histochem. 62 (3), 2943. 10.4081/ejh.2018.2943 PubMed DOI PMC

Rad S. K., Yeo K. K. L., Li R., Wu F., Liu S., Nourmohammadi S., et al. (2025). Enhancement of doxorubicin efficacy by bacopaside II in triple-negative breast cancer cells. Biomolecules 15, 55. 10.3390/biom15010055 PubMed DOI PMC

Ramos-Esquivel A., Víquez-Jaikel Á., Fernández C. (2017). Potential drug-drug and herb-drug interactions in patients with cancer: a prospective study of medication surveillance. JOP 13, e613–e622. 10.1200/JOP.2017.020859 PubMed DOI

Ravoori S., Vadhanam M. V., Aqil F., Gupta R. C. (2012). Inhibition of estrogen-mediated mammary tumorigenesis by blueberry and black raspberry. J. Agric. Food Chem. 60, 5547–5555. 10.1021/jf205325p PubMed DOI

Rodriguez-Barrueco R., Nekritz E. A., Bertucci F., Yu J., Sanchez-Garcia F., Zeleke T. Z., et al. (2017). miR-424(322)/503 is a breast cancer tumor suppressor whose loss promotes resistance to chemotherapy. Genes Dev. 31, 553–566. 10.1101/gad.292318.116 PubMed DOI PMC

Royston K. J., Udayakumar N., Lewis K., Tollefsbol T. O. (2017). A novel combination of withaferin A and sulforaphane inhibits epigenetic machinery, cellular viability and induces apoptosis of breast cancer cells. Int. J. Mol. Sci. 18, 1092. 10.3390/ijms18051092 PubMed DOI PMC

Rudzińska A., Juchaniuk P., Oberda J., Wiśniewska J., Wojdan W., Szklener K., et al. (2023). Phytochemicals in cancer treatment and cancer prevention—review on epidemiological data and clinical trials. Nutrients 15, 1896. 10.3390/nu15081896 PubMed DOI PMC

Samavat H., Dostal A. M., Wang R., Bedell S., Emory T. H., Ursin G., et al. (2015). The Minnesota Green Tea Trial (MGTT), a randomized controlled trial of the efficacy of green tea extract on biomarkers of breast cancer risk: study rationale, design, methods, and participant characteristics. Cancer Causes Control 26, 1405–1419. 10.1007/s10552-015-0632-2 PubMed DOI PMC

Samec M., Liskova A., Koklesova L., Mestanova V., Franekova M., Kassayova M., et al. (2019a). Fluctuations of histone chemical modifications in breast, prostate, and colorectal cancer: an implication of phytochemicals as defenders of chromatin equilibrium. Biomolecules 9, 829. 10.3390/biom9120829 PubMed DOI PMC

Samec M., Liskova A., Kubatka P., Uramova S., Zubor P., Samuel S. M., et al. (2019b). The role of dietary phytochemicals in the carcinogenesis via the modulation of miRNA expression. J. Cancer Res. Clin. Oncol. 145, 1665–1679. 10.1007/s00432-019-02940-0 PubMed DOI PMC

Seyhan A. A. (2019). Lost in translation: the valley of death across preclinical and clinical divide – identification of problems and overcoming obstacles. Transl. Med. Commun. 4, 18. 10.1186/s41231-019-0050-7 DOI

Shamsabadi F. T., Khoddami A., Fard S. G., Abdullah R., Othman H. H., Mohamed S. (2013). Comparison of tamoxifen with edible seaweed (Eucheuma cottonii L.) extract in suppressing breast tumor. Nutr. Cancer 65, 255–262. 10.1080/01635581.2013.756528 PubMed DOI

Sharma M., Tollefsbol T. O. (2022). Combinatorial epigenetic mechanisms of sulforaphane, genistein and sodium butyrate in breast cancer inhibition. Exp. Cell Res. 416, 113160. 10.1016/j.yexcr.2022.113160 PubMed DOI

Sharma P. C., Kalkal M. (2018). “Nutraceutical and medicinal importance of seabuckthorn (Hippophae sp.),” in Therapeutic, probiotic, and unconventional foods. Editors Grumezescu, A. M., Holban A. M. (Cambridge, MA: Academic Press; ), 227–253. 10.1016/B978-0-12-814625-5.00021-2 DOI

Singletary K., MacDonald C., Wallig M. (1996). Inhibition by rosemary and carnosol of 7,12-dimethylbenz[a]anthracene (DMBA)-induced rat mammary tumorigenesis and in vivo DMBA-DNA adduct formation. Cancer Lett. 104, 43–48. 10.1016/0304-3835(96)04227-9 PubMed DOI

Skrovankova S., Sumczynski D., Mlcek J., Jurikova T., Sochor J. (2015). Bioactive compounds and antioxidant activity in different types of berries. Int. J. Mol. Sci. 16, 24673–24706. 10.3390/ijms161024673 PubMed DOI PMC

Solár P., Sačková V., Hrčková G., Demečková V., Kassayová M., Bojková B., et al. (2017). Antitumor effect of the combination of manumycin A and Immodin is associated with antiplatelet activity and increased granulocyte tumor infiltration in a 4T1 breast tumor model. Oncol. Rep. 37, 368–378. 10.3892/or.2016.5265 PubMed DOI

Srivastava S. K., Arora S., Averett C., Singh S., Singh A. P. (2015). Modulation of MicroRNAs by phytochemicals in cancer: underlying mechanisms and translational significance. Biomed. Res. Int. 2015, 848710. 10.1155/2015/848710 PubMed DOI PMC

Tao L., Zhou Y., Luo Y., Qiu J., Xiao Y., Zou J., et al. (2024). Epigenetic regulation in cancer therapy: from mechanisms to clinical advances. MedComm – Oncol. 3, e59. 10.1002/mog2.59 DOI

Thapa D., Richardson A. J., Zweifel B., Wallace R. J., Gratz S. W. (2019). Genoprotective effects of essential oil compounds against oxidative and methylated DNA damage in human colon cancer cells. J. Food Sci. 84, 1979–1985. 10.1111/1750-3841.14665 PubMed DOI

Thomson C. A., Stendell-Hollis N. R., Rock C. L., Cussler E. C., Flatt S. W., Pierce J. P. (2007). Plasma and dietary carotenoids are associated with reduced oxidative stress in women previously treated for breast cancer. Cancer Epidemiol. Biomarkers Prev. 16, 2008–2015. 10.1158/1055-9965.EPI-07-0350 PubMed DOI PMC

Uramova S., Kubatka P., Dankova Z., Kapinova A., Zolakova B., Samec M., et al. (2018). Plant natural modulators in breast cancer prevention: status quo and future perspectives reinforced by predictive, preventive, and personalized medical approach. EPMA J. 9, 403–419. 10.1007/s13167-018-0154-6 PubMed DOI PMC

Verma V. K., Beevi S. S., Nair R. A., Kumar A., Kiran R., Alexander L. E., et al. (2024). MicroRNA signatures differentiate types, grades, and stages of breast invasive ductal carcinoma (IDC): miRNA-target interacting signaling pathways. Cell Commun. Signal. 22, 100. 10.1186/s12964-023-01452-2 PubMed DOI PMC

Visan S., Soritau O., Tatomir C., Baldasici O., Balacescu L., Balacescu O., et al. (2023). The bioactive properties of carotenoids from lipophilic sea buckthorn extract (Hippophae rhamnoides L.) in breast cancer cell lines. Molecules 28, 4486. 10.3390/molecules28114486 PubMed DOI PMC

Wang N., Wang Z., Wang Y., Xie X., Shen J., Peng C., et al. (2015). Dietary compound isoliquiritigenin prevents mammary carcinogenesis by inhibiting breast cancer stem cells through WIF1 demethylation. Oncotarget 6, 9854–9876. 10.18632/oncotarget.3396 PubMed DOI PMC

Wang Z., Zhao F., Wei P., Chai X., Hou G., Meng Q. (2022). Phytochemistry, health benefits, and food applications of sea buckthorn (Hippophae rhamnoides L.): a comprehensive review. Front. Nutr. 9, 1036295. 10.3389/fnut.2022.1036295 PubMed DOI PMC

Wei J., Li S., Su T., Zhao J., Jiang Y., Zubarev Y. A., et al. (2022). Phenolic compositions and antioxidant activities of Hippophae tibetana and H. rhamnoides ssp. sinensis berries produced in Qinghai-Tibet Plateau. Food Chem. X 15, 100397. 10.1016/j.fochx.2022.100397 PubMed DOI PMC

Xiang L.-P., Wang A., Ye J.-H., Zheng X.-Q., Polito C. A., Lu J.-L., et al. (2016). Suppressive effects of tea catechins on breast cancer. Nutrients 8, 458. 10.3390/nu8080458 PubMed DOI PMC

Yang F., Suo Y., Chen D., Tong L. (2016). Protection against vascular endothelial dysfunction by polyphenols in sea buckthorn berries in rats with hyperlipidemia. Biosci. Trends 10, 188–196. 10.5582/bst.2016.01056 PubMed DOI

Yang T., Xiao Y., Liu S., Luo F., Tang D., Yu Y., et al. (2023). Isorhamnetin induces cell cycle arrest and apoptosis by triggering DNA damage and regulating the AMPK/mTOR/p70S6K signaling pathway in doxorubicin-resistant breast cancer. Phytomedicine 114, 154780. 10.1016/j.phymed.2023.154780 PubMed DOI

Yang Y., Zhang M., Wang Y. (2022). The roles of histone modifications in tumorigenesis and associated inhibitors in cancer therapy. J. Natl. Cancer Cent. 2, 277–290. 10.1016/j.jncc.2022.09.002 PubMed DOI PMC

Yardley D. A., McCleod M., Schreiber F., Murphy P., Patton J., Thompson D. S., et al. (2010). A phase II trial of vinflunine as monotherapy or in combination with trastuzumab as first-line treatment of metastatic breast cancer. Cancer Invest 28, 925–931. 10.3109/07357907.2010.496755 PubMed DOI

Yu W., Li D., Zhang Y., Li C., Zhang C., Wang L. (2019). MiR-142-5p acts as a significant regulator through promoting proliferation, invasion, and migration in breast cancer modulated by targeting SORBS1. Technol. Cancer Res. Treat. 18, 1533033819892264. 10.1177/1533033819892264 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

Zhang Y., Han X.-X., Lin X.-M., Li Z., Zhang J.-H. (2022). miR-450a exerts oncosuppressive effects in breast carcinoma by targeting CREB1. Kaohsiung J. Med. Sci. 38, 643–652. 10.1002/kjm2.12547 PubMed DOI PMC