University of Wisconsin Carbone Cancer Center, United States.
Departments of Pharmacology and Hematology & Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, United States.
Biochem Pharmacol. 2018 Aug;154:407-413. doi: 10.1016/j.bcp.2018.05.019. Epub 2018 May 31.
Breast cancer continues to be the most commonly diagnosed malignancy and second most common cause of cancer-related deaths among women in the United States. Improved understanding of the molecular heterogeneity of breast tumors and the approval of multiple targeted therapies have revolutionized the treatment landscape and long-term survival rates for patients with breast cancer. Despite the development of highly effective targeted agents, drug resistance and disease progression remain major clinical concerns. Improved understanding of the molecular mechanisms mediating drug resistance will allow new treatments to be developed. The forkhead box M1 (FoxM1) transcription factor is overexpressed in breast cancer and strongly associated with resistance to targeted therapies and chemotherapy. FoxM1 regulates all hallmarks of cancer, including proliferation, mitosis, EMT, invasion, and metastasis. Inhibition of FoxM1 transcription factor function is a potential strategy for overcoming breast cancer progression. In this research update, we review the role of FoxM1 in breast cancer and pharmacological approaches for blocking FoxM1 transcription factor function. Future preclinical studies should evaluate combination drug strategies to inhibit FoxM1 function and upstream kinase signaling pathways as potential strategies to treat resistant and metastatic breast cancers.
乳腺癌仍然是美国女性中最常见的恶性肿瘤，也是癌症相关死亡的第二大常见原因。对乳腺癌肿瘤分子异质性的认识不断提高，以及多种靶向治疗药物的批准，彻底改变了乳腺癌患者的治疗前景和长期生存率。尽管开发了高度有效的靶向药物，但耐药性和疾病进展仍然是主要的临床关注点。深入了解介导耐药性的分子机制将有助于开发新的治疗方法。叉头框 M1（FoxM1）转录因子在乳腺癌中过度表达，与对靶向治疗和化疗的耐药性密切相关。FoxM1 调节癌症的所有标志性特征，包括增殖、有丝分裂、上皮间质转化、侵袭和转移。抑制 FoxM1 转录因子功能是克服乳腺癌进展的潜在策略。在本研究更新中，我们回顾了 FoxM1 在乳腺癌中的作用以及抑制 FoxM1 转录因子功能的药理学方法。未来的临床前研究应评估联合药物策略，以抑制 FoxM1 功能和上游激酶信号通路，作为治疗耐药性和转移性乳腺癌的潜在策略。
