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  • TOP2A in Breast and Ovarian Cancer: From a Proliferation Marker to a Potential Mediator of Chemoresistance

  • Zahra Mohammadi,1 Fatimah RahimiyanZade,2 Fatemeh Mahmoodi,3,*
    1. Shahrekord UniversityShahrekord University
    2. Shahrekord University


  • Introduction: Breast cancer is the most common malignancy among women worldwide, while ovarian cancer remains the most lethal gynecological malignancy, with nearly 70% of patients diagnosed at advanced stages. Despite histological differences, both tumors share estrogen responsiveness and a hereditary association with BRCA1/2 mutations. Among topoisomerases, TOP2A (topoisomerase II alpha), located on chromosome 17q21.2, has attracted considerable attention. By controlling DNA topology, it enables correct chromosome segregation during mitosis, and its genomic proximity to HER2 underscores its relevance in breast cancer genetics. In breast cancer, TOP2A is a direct target of anthracycline-based drugs; co-amplification of TOP2A, rather than HER2 amplification alone, has been identified as a clinically useful predictive marker of anthracycline response. In ovarian cancer, high TOP2A expression has been associated with lower overall survival and increased proliferation through the AKT/mTOR pathway, and TOP2A knockdown has been shown to restore cisplatin sensitivity in resistant high-grade serous ovarian cancer cells by activating ferroptosis through the TP53/GPX4/SLC7A11 axis. This narrative review summarizes current evidence regarding TOP2A expression, prognostic value, and its role in treatment response and drug resistance in breast and ovarian cancer.
  • Methods: This narrative, non-systematic review searched PubMed, Scopus, and Web of Science for English-language articles published between 2015 and 2025. Keywords included TOP2A, breast cancer, ovarian cancer, prognosis, survival, drug resistance, anthracycline, and cisplatin. Articles were selected based on their relevance to TOP2A expression, prognostic value, and resistance mechanisms in the two cancers, and reference lists were manually screened. Six primary studies reporting clinical or mechanistic data were included for qualitative synthesis.
  • Results: In breast cancer, among patients with early or locally advanced disease treated with anthracycline-based neoadjuvant chemotherapy, HER2-overexpressing tumors with concurrent high TOP2A amplification had a significantly higher pathological complete response rate than those with low or no TOP2A amplification (56.3% vs. 13.8%, P = 0.001). In ovarian cancer, high TOP2A expression was associated with lower overall survival, particularly in the serous subtype. TOP2A knockdown inhibited proliferation and induced G1-phase arrest through the AKT/mTOR pathway in vitro and in xenograft models. In platinum-resistant recurrent disease, higher TOP2A gene copy number was associated with improved response to pegylated liposomal doxorubicin. More recently, TOP2A knockdown restored cisplatin sensitivity in resistant ovarian cancer cells by activating ferroptosis and suppressing epithelial-mesenchymal transition through a TOP2A–TP53 interaction regulating the GPX4/SLC7A11 axis. These findings indicate a context-dependent relationship between TOP2A and treatment response: in breast cancer, TOP2A mainly predicts anthracycline response alongside HER2 amplification, whereas in ovarian cancer its role extends to proliferation and mechanisms associated with platinum resistance.
  • Conclusion: TOP2A functions as more than a marker of cell proliferation, demonstrating a context-dependent relationship with treatment response and drug resistance. Its relevance differs according to cancer type and therapeutic agent, involving HER2 proximity and anthracycline sensitivity in breast cancer and AKT/mTOR-driven proliferation together with ferroptosis-related cisplatin sensitivity in ovarian cancer. These findings position TOP2A as a potential candidate for patient stratification and therapeutic targeting; however, prospective clinical validation remains limited.
  • Keywords: TOP2A, Breast Cancer, Ovarian Cancer, Drug Resistance, Biomarker

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