Pérez-Chacón Gema, Santamaría Patricia G, Redondo-Pedraza Jaime, González-Suárez Eva
Molecular Oncology, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
Oncobell, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
Adv Exp Med Biol. 2025;1464:309-345. doi: 10.1007/978-3-031-70875-6_16.
RANK pathway has attracted increasing interest as a promising target in breast cancer, given the availability of denosumab, an anti-RANKL drug. RANK signaling mediates progesterone-driven regulation of mammary gland development and favors breast cancer initiation by controlling mammary cell proliferation and stem cell fate. RANK activation promotes luminal mammary epithelial cell senescence, acting as an initial barrier to tumorigenesis but ultimately facilitating tumor progression and metastasis. Comprehensive analyses have demonstrated that RANK protein expression is an independent biomarker of poor prognosis in postmenopausal and estrogen receptor-negative breast cancer patients. RANK pathway also has multiple roles in immunity and inflammation, regulating innate and adaptive responses. In the tumor microenvironment, RANK and RANKL are expressed by different immune cell populations and contribute to the regulation of tumor immune surveillance, mainly driving immunosuppressive effects.Herein, we discuss the preventive and therapeutic potential of targeting RANK signaling in breast cancer given its tumor cell intrinsic and extrinsic effects. RANKL inhibition has been shown to induce mammary tumor cell differentiation and an antitumor immune response. Moreover, loss of RANK signaling increases sensitivity of breast cancer cells to chemotherapy, targeted therapies such as HER2 and CDK4/6 inhibitors, and immunotherapy. Finally, we describe clinical trials of denosumab for breast cancer prevention, such as those ongoing in women with high risk of developing breast cancer, large phase III clinical trials where the impact of adjuvant denosumab on disease-free survival has been assessed, and window trials to evaluate the immunomodulatory effects of denosumab in breast cancer and other solid tumors.
鉴于抗RANKL药物地诺单抗的可用性，RANK通路作为乳腺癌中一个有前景的靶点已引起越来越多的关注。RANK信号介导孕酮驱动的乳腺发育调节，并通过控制乳腺细胞增殖和干细胞命运促进乳腺癌的发生。RANK激活促进乳腺腔上皮细胞衰老，这是肿瘤发生的初始屏障，但最终会促进肿瘤进展和转移。综合分析表明，RANK蛋白表达是绝经后和雌激素受体阴性乳腺癌患者预后不良的独立生物标志物。RANK通路在免疫和炎症中也具有多种作用，调节先天性和适应性反应。在肿瘤微环境中，RANK和RANKL由不同的免疫细胞群体表达，并有助于调节肿瘤免疫监视，主要发挥免疫抑制作用。在此，我们讨论鉴于RANK信号在肿瘤细胞内在和外在的作用，其在乳腺癌预防和治疗方面的潜力。RANKL抑制已被证明可诱导乳腺肿瘤细胞分化和抗肿瘤免疫反应。此外，RANK信号的缺失增加了乳腺癌细胞对化疗、HER2和CDK4/6抑制剂等靶向治疗以及免疫治疗的敏感性。最后，我们描述了地诺单抗用于乳腺癌预防的临床试验，例如在有患乳腺癌高风险的女性中正在进行的试验、评估辅助性地诺单抗对无病生存影响的大型III期临床试验，以及评估地诺单抗在乳腺癌和其他实体瘤中免疫调节作用的窗口期试验。
