Quercetin as a Multi-Targeted Therapeutic Agent in Breast Cancer: Molecular Targets and Therapeutic Potential

Commentary Written by Dave James, ND, Licensed Naturopathic Physician, WA, NH, CT & AZ. Quercetin demonstrates substantial promise as a multi-targeted therapeutic agent in breast cancer through the regulation of key signaling pathways, modulation of non-coding RNAs, reversal of drug resistance, and synergy with conventional and targeted therapies. 

women with pink shirts for breast cancerBreast cancer remains one of the most commonly diagnosed malignancy among women worldwide and a leading cause of cancer-related mortality, despite substantial advances in screening, molecular subtyping, and targeted therapies. Current treatment paradigms—including surgery, chemotherapy, endocrine therapy, HER2-targeted agents, and CDK4/6 inhibitors—have significantly improved survival outcomes; however, therapeutic  resistance, toxicity, and recurrence remain major clinical challenges. These limitations underscore the urgent need for adjunctive or combinational therapies strategies capable of modulating multiple oncogenic pathways. Quercetin, a naturally occurring flavonol widely distributed in fruits, vegetables, and medicinal plants, has emerged as a promising multi-targeted compound with pleiotropic effects relevant to breast cancer biology 1-4. This is not medical advice, but if I were trapped on a desert island and had to take only one supplement with me, I would choose Quercetin. However, please consult with your licensed healthcare provider for your specific case.

Mechanistic investigations have demonstrated that quercetin influences several key intracellular signaling networks implicated in breast cancer progression. Preclinical models consistently show that quercetin downregulates PI3K/Akt/mTOR pathway,  suppressing cell growth, proliferation and survival mechanisms commonly upregulated in endocrine-resistant and triple-negative breast cancer models 1,5. In parallel, quercetin inhibits the Wnt/β-catenin cascade, a critical regulator of tumor stemness, cancer cell renewal, and metastatic potential 1,6.Quercetin has also been shown to attenuateJAK/STAT signaling, which contributes to inflammatory cytokine-driven tumor progression and pro-inflammatory signaling within the tumor microenvironment1,7. Additionally,quercetin  activates AMP-activated protein kinase (AMPK), contributing to metabolic stress , autophagy induction, and reduced proliferation in multiple breast cancer lines1,5,8. These pathways are the holy grails that academic oncology and big pharma are chasing. Through these combined effects, quercetin demonstrates the capacity to not only suppress tumor growth but also sensitize breast cancer cells to conventional chemotherapeutic agents such as doxorubicin (aka “the red devil” nicknamed so for its red color), paclitaxel (derived and synthetically manufactured based off the Pacific yew tree Taxus brevifolia), and cisplatin (a platinum-based drug known for it’s ear toxicity).

Beyond intracellular signaling, quercetin exerts significant epigenetic (above the genome level) and post-transcriptional regulation. Studies show that quercetin influences non-coding RNAs, including microRNAs and long non-coding RNAs, that govern tumor proliferation, apoptosis (programmed cell death), EMT, and chemoresistance1,9-11. Through these modulatory effects on the transcriptome highlight quercetin’s role in reprogramming cancer cell phenotypes at multiple levels of regulation. Importantly, preclinical data suggest that quercetin may overcome multidrug resistance by inhibiting efflux pumps such as P-glycoprotein and modulating drug-metabolizing enzymes, enhancing intracellular accumulation of chemotherapeutic agents6,12. Such properties may position quercetin as a valuable adjuvant in chemo-resistant breast cancer although clinical validation is still lacking

In addition to direct cytotoxic and chemosensitizing effects, quercetin exerts robust pro-apoptotic, anti-invasive, and anti-inflammatory effects e. Quercetin has been shown to promote mitochondrial-mediated apoptosis, increase Bax/Bcl-2 ratios, cytochrome c release, and caspase-dependent pathways across multiple preclinical breast cancer models8. Simultaneously, quercetin reduces NF-κB activity and associated pro-inflammatory cytokines, a mechanism particularly relevant to the tumor-promoting microenvironment in triple-negative breast cancer (TNBC)7,13. In my clinical practice, I monitor a blood lab called a complete metabolic panel when I use high dose quercetin in the stage 4 breast cancer patients I care for where I utilize this therapy via IV for supportive care alongside standard of care safely separated by 24 hours on either side of chemotherapy or immunotherapy. These effects collectively contribute to quercetin’s role in suppressing metastatic potential and modulating immune surveillance.

Notably, quercetin exhibits synergistic effects when combined with emerging targeted therapies. While data are preclinical, several studies indicate that quercetin  enhance the efficacy of CDK4/6 inhibitors, attenuate estrogen receptor cross-talk in hormone-positive tumors, and modulate HER2-associated signaling pathways in HER2-positive models 3,14,15. Thesebroad-spectrum activities align with the concept of quercetin as a “network pharmacology” agent, capable of simultaneously addressing multiple vulnerabilities in breast cancer.

Despite these compelling mechanistic and preclinical evidence, translation of quercetin  into clinical oncology remains limited. Key challenges include it’s poor oral bioavailability, rapid metabolism, and variable systemic exposure. To address these limitations, nanoparticle-based delivery systems, liposomal formulations, and conjugation with phospholipids or polysaccharides have been explored, demonstrating improved stability, bioavailability and therapeutic index in preclinical models2,16-18. Furthermore, safety data in humans suggest that quercetin is well tolerated at dietary and supplemental doses, though standardized dosing and long-term effects in cancer populations require clarification.

The potential integration of quercetin into breast cancer management highlights broader implications for precision naturopathic oncology. As a dietary flavonoid with low toxicity and broad pathway modulation, quercetin represents a model for how phytochemicals may complement conventional cancer treatment strategies. Continued preclinical exploration, coupled with rigorously designed early-phase clinical trials, is needed to establish optimal formulations, dosing, and synergistic combinations that may enhance future therapeutic applications. Such efforts may ultimately position quercetin as both a preventive and therapeutic adjunct in the evolving landscape of breast cancer management.

In conclusion, quercetin demonstrates substantial promise as a multi-targeted therapeutic agent in breast cancer through the regulation of key signaling pathways, modulation of non-coding RNAs, reversal of drug resistance, and synergy with conventional and targeted therapies. While clinical translation is still in early stages, advances in drug delivery and bioavailability may accelerate its integration into combinational treatment strategies. Quercetin exemplifies the therapeutic potential of phytochemicals as safe, effective, and mechanistically diverse agents in the fight against breast cancer.

Source: Hjazi, Ahmed, Sumaya Nadhim Mohammed, Munthar Kadhim Abosaoda, Irfan Ahmad, M. M. Rekha, Mayank Kundlas, Muhammad Ikram Ullah, Baydaa Abd, Subhashree Ray, and Deepak Nathiya. “Quercetin as a multi-targeted therapeutic agent in breast cancer: molecular targets and therapeutic potential.” Medical Oncology 42, no. 8 (2025): 365.

Posted December 3, 2025.

Dave James, ND, is a licensed naturopathic physician in Connecticut and Arizona and a proud alumnus and former Board of Trustees member of Sonoran University of Health Sciences. Dr. James focuses on chronic pain and supportive care for persons with a diagnosis of cancer, including survivorship. He now delivers CME presentations alongside patient care. Deeply committed to public health and equity, Dr. James is a passionate advocate for expanding licensure for naturopathic physicians nationwide so that all patients—regardless of socioeconomic status—can access high-quality, evidence-informed integrative care. He believes the doctor–patient relationship is sacred and central to healing.

Reference:

  1. Hjazi A, Mohammed SN, Abosaoda MK, et al. Quercetin as a multi-targeted therapeutic agent in breast cancer: molecular targets and therapeutic potential. Med Oncol. Jul 22 2025;42(8):365. doi:10.1007/s12032-025-02907-x
  2. Wu ZY, Qiu KY, Gai YJ, Wu JH, Zhou BX, Shi QF. Quercetin: A Natural Ally in Combating Breast Cancer. Int J Nanomedicine. 2025;20:9155–9177. doi:10.2147/ijn.S518174
  3. Almatroodi SA, Alsahli MA, Almatroudi A, et al. Potential Therapeutic Targets of Quercetin, a Plant Flavonol, and Its Role in the Therapy of Various Types of Cancer through the Modulation of Various Cell Signaling Pathways. Molecules (Basel, Switzerland). Mar 1 2021;26(5)doi:10.3390/molecules26051315
  4. Maugeri A, Calderaro A, Patanè GT, et al. Targets Involved in the Anti-Cancer Activity of Quercetin in Breast, Colorectal and Liver Neoplasms. Int J Mol Sci. Feb 2 2023;24(3)doi:10.3390/ijms24032952
  5. Jiang J, Yang Y, Wang F, Mao W, Wang Z, Liu Z. Quercetin inhibits breast cancer cell proliferation and survival by targeting Akt/mTOR/PTEN signaling pathway. Chem Biol Drug Des. Jun 2024;103(6):e14557. doi:10.1111/cbdd.14557
  6. Li S, Zhao Q, Wang B, Yuan S, Wang X, Li K. Quercetin reversed MDR in breast cancer cells through down-regulating P-gp expression and eliminating cancer stem cells mediated by YB-1 nuclear translocation. Phytotherapy research : PTR. Aug 2018;32(8):1530–1536. doi:10.1002/ptr.6081
  7. Fang L, Gao D, Wang T, Zhao H, Zhang Y, Wang S. From nature to clinic: Quercetin’s role in breast cancer immunomodulation. Front Immunol. 2024;15:1483459. doi:10.3389/fimmu.2024.1483459
  8. Biswas P, Dey D, Biswas PK, et al. A Comprehensive Analysis and Anti-Cancer Activities of Quercetin in ROS-Mediated Cancer and Cancer Stem Cells. Int J Mol Sci. Oct 4 2022;23(19)doi:10.3390/ijms231911746
  9. Sultan A, Khalil M, Samy B, Alkhuriji A, Sadek O. Quercetin induces apoptosis in triple-negative breast cancer cells via inhibiting fatty acid synthase and ß-catenin. 01/01 2017;10:156–172.
  10. Zhao Y, Yu Z, Ma R, et al. lncRNA-Xist/miR-101-3p/KLF6/C/EBPα axis promotes TAM polarization to regulate cancer cell proliferation and migration. Mol Ther Nucleic Acids. Mar 5 2021;23:536–551. doi:10.1016/j.omtn.2020.12.005
  11. Liang Y, Song X, Li Y, et al. LncRNA BCRT1 promotes breast cancer progression by targeting miR-1303/PTBP3 axis. Mol Cancer. May 8 2020;19(1):85. doi:10.1186/s12943-020-01206-5
  12. Ye Q, Liu K, Shen Q, et al. Reversal of Multidrug Resistance in Cancer by Multi-Functional Flavonoids. Review. Frontiers in Oncology. 2019–June–12 2019;Volume 9 – 2019doi:10.3389/fonc.2019.00487
  13. Cao L, Yang Y, Ye Z, et al. Quercetin‑3‑methyl ether suppresses human breast cancer stem cell formation by inhibiting the Notch1 and PI3K/Akt signaling pathways Corrigendum in /10.3892/ijmm.2025.5650. International journal of molecular medicine. 2018/09/01 2018;42(3):1625–1636. doi:10.3892/ijmm.2018.3741
  14. Pawar CS, Balamurugan K, Baskar S, Prasad NR, Khan HA. Enhancing Chemosensitivity in Drug-Resistant Breast Cancer Cells Using β-Cyclodextrin-Loaded Quercetin and Doxorubicin Inclusion Complex via Modulating SRC/PI3K/Akt Pathway. Applied Biochemistry and Biotechnology. 2025/06/01 2025;197(6):4068–4095. doi:10.1007/s12010-025-05219-y
  15. Prieto-Vila M, Shimomura I, Kogure A, et al. Quercetin Inhibits Lef1 and Resensitizes Docetaxel-Resistant Breast Cancer Cells. Molecules (Basel, Switzerland). Jun 1 2020;25(11)doi:10.3390/molecules25112576
  16. Hatami M, Kouchak M, Kheirollah A, Khorsandi L, Rashidi M. Quercetin-loaded solid lipid nanoparticles exhibit antitumor activity and suppress the proliferation of triple-negative MDA-MB 231 breast cancer cells: implications for invasive breast cancer treatment. Molecular Biology Reports. 2023/11/01 2023;50(11):9417–9430. doi:10.1007/s11033-023-08848-w
  17. Samantaray A, Pradhan D, Nayak NR, et al. Nanoquercetin based nanoformulations for triple negative breast cancer therapy and its role in overcoming drug resistance. Discover Oncology. 2024/09/17 2024;15(1):452. doi:10.1007/s12672-024-01239-y
  18. Tiburzi S, Lezcano V, Principe G, et al. Quercetin-loaded magnetic nanoparticles: a promising tool for antitumor treatment in human breast cancer cells. J Drug Target. Aug 2025;33(7):1227–1242. doi:10.1080/1061186x.2025.2477764

 

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