Das Gokul M, Oturkar Chetan C, Menon Vishnu
Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA.
Endocrinology. 2025 Feb 5;166(3). doi: 10.1210/endocr/bqaf020.
Tamoxifen is one of the most widely used anticancer drugs in the world. It is a safe drug with generally well-tolerated side effects and has been prescribed for the treatment of early-stage and advanced-stage or metastatic estrogen receptor α (ERα/ESR1)-positive breast cancer. Tamoxifen therapy also provides a 38% reduction of the risk of developing breast cancer in women at high risk. With the advent of newer medications targeting ERα-positive breast cancer, tamoxifen is now mainly used as adjuvant therapy for lower-risk premenopausal breast cancer and cancer prevention. It is widely accepted that tamoxifen as a selective estrogen receptor modulator exerts its therapeutic effect by competitively binding to ERα, leading to the recruitment of corepressors and inhibition of transcription of genes involved in the proliferation of breast cancer epithelium. As such, expression of ERα in breast tumors has been considered necessary for tumors to be responsive to tamoxifen therapy. However, ERα-independent effects of tamoxifen in various in vitro and in vivo contexts have been reported over the years. Importantly, the recent discovery that ERα and estrogen receptor β (ERβ/ESR2) can bind tumor suppressor protein p53 with functional consequences has provided new insights into the mechanisms underlying response to tamoxifen therapy and resistance. Furthermore, these findings have paved the way for broadening the use of tamoxifen by potentially repurposing it to treat triple negative (negative for ERα, human epidermal growth factor receptor 2, and progesterone receptor) breast cancer. Herein, we summarize these developments and discuss their mechanistic underpinnings and clinical implications.
他莫昔芬是世界上使用最广泛的抗癌药物之一。它是一种安全的药物，副作用通常耐受性良好，已被用于治疗早期、晚期或转移性雌激素受体α（ERα/ESR1）阳性乳腺癌。他莫昔芬治疗还可使高危女性患乳腺癌的风险降低38%。随着针对ERα阳性乳腺癌的新型药物的出现，他莫昔芬现在主要用作低风险绝经前乳腺癌的辅助治疗和癌症预防。人们普遍认为，他莫昔芬作为一种选择性雌激素受体调节剂，通过竞争性结合ERα发挥其治疗作用，导致共抑制因子的募集和对参与乳腺癌上皮细胞增殖的基因转录的抑制。因此，乳腺肿瘤中ERα的表达被认为是肿瘤对他莫昔芬治疗产生反应所必需的。然而，多年来已有报道称他莫昔芬在各种体外和体内环境中存在不依赖ERα的作用。重要的是，最近发现ERα和雌激素受体β（ERβ/ESR2）可以与肿瘤抑制蛋白p53结合并产生功能后果，这为他莫昔芬治疗反应和耐药性的潜在机制提供了新的见解。此外，这些发现为扩大他莫昔芬的用途铺平了道路，有可能将其重新用于治疗三阴性（ERα、人表皮生长因子受体2和孕激素受体均为阴性）乳腺癌。在此，我们总结了这些进展，并讨论了其机制基础和临床意义。
