Georgia Cancer Center, Augusta University, Augusta, GA, United States.
Department of Cellular Biology & Anatomy, Medical College of Georgia at Augusta University, Augusta, GA, United States.
Front Endocrinol (Lausanne). 2024 Mar 18;15:1298423. doi: 10.3389/fendo.2024.1298423. eCollection 2024.
Estrogen receptor positive (ER) breast cancer is the most common breast cancer diagnosed annually in the US with endocrine-based therapy as standard-of-care for this breast cancer subtype. Endocrine therapy includes treatment with antiestrogens, such as selective estrogen receptor modulators (SERMs), selective estrogen receptor downregulators (SERDs), and aromatase inhibitors (AIs). Despite the appreciable remission achievable with these treatments, a substantial cohort of women will experience primary tumor recurrence, subsequent metastasis, and eventual death due to their disease. In these cases, the breast cancer cells have become resistant to endocrine therapy, with endocrine resistance identified as the major obstacle to the medical oncologist and patient. To combat the development of endocrine resistance, the treatment options for ER, HER2 negative breast cancer now include CDK4/6 inhibitors used as adjuvants to antiestrogen treatment. In addition to the dysregulated activity of CDK4/6, a plethora of genetic and biochemical mechanisms have been identified that contribute to endocrine resistance. These mechanisms, which have been identified by lab-based studies utilizing appropriate cell and animal models of breast cancer, and by clinical studies in which gene expression profiles identify candidate endocrine resistance genes, are the subject of this review. In addition, we will discuss molecular targeting strategies now utilized in conjunction with endocrine therapy to combat the development of resistance or target resistant breast cancer cells. Of approaches currently being explored to improve endocrine treatment efficacy and patient outcome, two adaptive cell survival mechanisms, autophagy, and "reversible" senescence, are considered molecular targets. Autophagy and/or senescence induction have been identified in response to most antiestrogen treatments currently being used for the treatment of ER breast cancer and are often induced in response to CDK4/6 inhibitors. Unfortunately, effective strategies to target these cell survival pathways have not yet been successfully developed. Thus, there is an urgent need for the continued interrogation of autophagy and "reversible" senescence in clinically relevant breast cancer models with the long-term goal of identifying new molecular targets for improved treatment of ER breast cancer.
雌激素受体阳性（ER）乳腺癌是美国每年诊断出的最常见乳腺癌，内分泌治疗是这种乳腺癌亚型的标准治疗方法。内分泌治疗包括使用抗雌激素药物，如选择性雌激素受体调节剂（SERMs）、选择性雌激素受体下调剂（SERDs）和芳香化酶抑制剂（AIs）。尽管这些治疗方法可以实现相当可观的缓解，但相当一部分女性会因疾病而经历原发性肿瘤复发、随后转移和最终死亡。在这些情况下，乳腺癌细胞对内分泌治疗产生了耐药性，内分泌耐药被认为是肿瘤内科医生和患者的主要障碍。为了对抗内分泌耐药的发展，现在 ER、HER2 阴性乳腺癌的治疗选择包括 CDK4/6 抑制剂，作为抗雌激素治疗的辅助药物。除了 CDK4/6 的失调活性外，还确定了许多遗传和生化机制有助于内分泌耐药。这些机制已经通过利用适当的乳腺癌细胞和动物模型的实验室研究以及通过基因表达谱识别候选内分泌耐药基因的临床研究来确定，是本综述的主题。此外，我们将讨论目前与内分泌治疗联合使用的分子靶向策略，以对抗耐药的发展或针对耐药的乳腺癌细胞。在目前正在探索的改善内分泌治疗效果和患者预后的方法中，两种适应性细胞存活机制，自噬和“可逆”衰老，被认为是分子靶点。自噬和/或衰老诱导已被确定为对目前用于治疗 ER 乳腺癌的大多数抗雌激素治疗的反应，并且经常对 CDK4/6 抑制剂产生反应。不幸的是，针对这些细胞存活途径的有效策略尚未成功开发。因此，迫切需要在具有临床相关性的乳腺癌模型中继续研究自噬和“可逆”衰老，长期目标是确定改善 ER 乳腺癌治疗的新分子靶点。
