p53转录因子是一个重要的细胞过程调节器，当遭受基因毒性压力时，p53会被激活以促进DNA修复、细胞周期停滞和细胞凋亡。在乳腺癌中，p53的肿瘤抑制活性常常被其负调控因子MDM2的过表达或突变所失活，这在所有乳腺癌病例中占30-35%左右。值得注意的是，在乳腺癌中，p53突变的频率高度依赖亚型，大多数激素受体阳性或基底样亚型保留了野生型p53状态，而激素受体阴性患者主要携带p53突变，并具有增益功能致癌活动，这会导致较差的预后。因此，针对不同亚型乳腺癌中的野生型和突变型p53的双重策略可能具有临床意义。最近几年，针对p53的治疗方案得到了快速进展，包括独特的小分子化学抑制剂、定位肽、PROTACs以及使用载体和工程抗体的几种基因治疗方法。本文重点介绍正在临床前和临床开发中的治疗策略，以克服野生型和突变型p53在乳腺肿瘤中的失活，并讨论它们在临床前和临床环境中的有效性和局限性。©作者

The transcription factor p53 is an important regulator of a multitude of cellular processes. In the presence of genotoxic stress, p53 is activated to facilitate DNA repair, cell cycle arrest, and apoptosis. In breast cancer, the tumor suppressive activities of p53 are frequently inactivated by either the overexpression of its negative regulator MDM2, or mutation which is present in 30-35% of all breast cancer cases. Notably, the frequency of p53 mutation is highly subtype dependent in breast cancers, with majority of hormone receptor-positive or luminal subtypes retaining the wild-type p53 status while hormone receptor-negative patients predominantly carry p53 mutations with gain-of-function oncogenic activities that contribute to poorer prognosis. Thus, a two-pronged strategy of targeting wild-type and mutant p53 in different subtypes of breast cancer can have clinical relevance. The development of p53-based therapies has rapidly progressed in recent years, and include unique small molecule chemical inhibitors, stapled peptides, PROTACs, as well as several genetic-based approaches using vectors and engineered antibodies. In this review, we highlight the therapeutic strategies that are in pre-clinical and clinical development to overcome p53 inactivation in both wild-type and mutant p53-bearing breast tumors, and discuss their efficacies and limitations in pre-clinical and clinical settings.© The author(s).