人类细胞色素P450 1B1（CYP1B1）催化雌激素代谢产生促进乳腺癌进展的代谢物。由于癌细胞的浸润特性导致癌症复发，极大地降低了患者的生存率，我们研究了CYP1B1在乳腺癌中涉及的新的促浸润机制。通过探索侵袭性乳腺癌患者的临床数据，发现CYP1B1与尿激酶型纤溶酶原活化物受体（uPAR）呈潜在相关性。有趣的是，uPAR mRNA表达水平在携带有驱动突变TP53基因的侵袭性乳腺癌患者中升高，并且我们的结果显示CYP1B1在p53的突变状态下通过调控激活了uPAR通路。CYP1B1抑制了野生型（WT）p53，而通过转录调控、蛋白稳定化和p53R280K在Ser15残基磷酸化后的激活则诱导了致癌增强型突变体p53R280K。有趣的是，CYP1B1多态基因研究和4-羟基雌二醇（4-OHE2）处理结果表明，CYP1B1通过其酶活性调节p53和uPAR。此外，DMBA和TMS对uPAR表达的影响在HCT116p53-/-细胞中消失，表明p53对于CYP1B1诱导uPAR是至关重要的。总之，我们的结果表明CYP1B1可能通过调控p53基因突变状态和进一步激活uPAR通路，在癌细胞中诱导侵袭特征，从而降低乳腺癌患者的不复发生存率。对CYP1B1以前未知的分子机制的阐明，可能为针对癌症侵袭进展的有效抗癌治疗策略的开发提供证据。 版权所有 © 2023. Elsevier B.V.出版。

Human cytochrome P450 1B1 (CYP1B1) catalyzes estrogen metabolism to produce metabolites that promote the progression of breast cancer. Since the invasive properties of cancer cells cause cancer relapse, which dramatically reduces patient survival, we investigated the new pro-invasive mechanism involving CYP1B1 in breast cancer. Exploring clinical data from invasive breast cancer patients revealed that CYP1B1 exhibits a potential correlation with urokinase-type plasminogen activator receptor (uPAR). Interestingly, uPAR mRNA expression was elevated in invasive breast cancer patients carrying TP53 genes with driver mutations, and our results showed that CYP1B1 activates the uPAR pathway following regulation of p53 according to its mutant status. CYP1B1 suppressed wild-type (WT) p53 whereas it induced the oncogenic gain-of-function mutant p53R280K, not only via transcriptional regulation but also the protein stabilization and activation following phosphorylation on Ser15 residue of p53R280K. Intriguingly, results from CYP1B1 polymorphic gene study and 4-hydroxyestradiol (4-OHE2) treatment showed that CYP1B1 regulates p53s and uPAR through its enzymatic activity. Furthermore, effects of DMBA and TMS on uPAR expression disappeared in HCT116p53-/- cells, indicating that p53 is critical for uPAR induction by CYP1B1. Collectively, our results demonstrate that CYP1B1 may reduce the relapse-free survival rate of breast cancer patients by inducing invasive traits in cancer cells via p53 regulation based on the mutation status of TP53 genes and further activation of the uPAR pathway. The elucidation of the previously unknown molecular mechanism of CYP1B1 may provide evidence for the development of effective anti-cancer therapeutic strategies that target the progression of cancer invasion.Copyright © 2023. Published by Elsevier B.V.