Wang Jing, Zhang Shasha, Zhang Jiaxin, Zhang Zhongliang, Ma Qinglong, Fu Wenkang, Chen Xiaohua, Zhao Dapeng, Zhao Meie, Di Cuixia, Xie Xiaodong
School of Basic Medical Sciences, Lanzhou University Lanzhou 730000, Gansu, China.
Bio-Medical Research Center, Institute of Modern Physics, Chinese Academy of Sciences Lanzhou 730000, Gansu, China.
Am J Cancer Res. 2023 Jan 15;13(1):86-104. eCollection 2023.
Phosphatase and tensin homolog () is one of the most important tumor suppressor genes. Although studies have shown the association between cancer and genetic polymorphisms of , the underlying molecular mechanisms of breast cancer (BC) chemosensitivity that results from polymorphism is still unclear. This study aims to investigate potential links between polymorphisms in cis-regulatory elements and BC chemosensitivity in the Chinese population. A total of 172 BC patients who received neoadjuvant chemotherapy were included in the study, including 104 chemosensitive cases and 68 chemoresistant cases. The results showed a significant association between the rs786204926 polymorphism and BC chemosensitivity. Logistic multivariate regression analysis showed that age, lymph node metastasis, and the rs786204926 genotype were risk factors for BC chemoresistance. The G allele of rs786204926 is more prone to increasing the risk of chemosensitivity in BC. Additionally, analysis using Alamut Visual showed a preference of the G allele of rs786204926 to produce a novel PTEN mutant with an insertion of 18 bases from intron 4. While the transcriptional level of PTEN remained similar in chemosensitivity and chemoresistant samples, its protein level changed significantly. Interestingly, there were significant differences in both transcription and protein levels of the novel PTEN mutant between the two groups. Furthermore, we found that the mutant was more susceptible to dephosphorylation compared with wildtype PTEN, leading to chemosensitivity through the PI3K-AKT signaling pathway. These findings indicate that novel PTEN mutants caused by polymorphisms in cis-regulatory elements may be involved in BC chemosensitivity.
磷酸酶与张力蛋白同源物（PTEN）是最重要的肿瘤抑制基因之一。尽管研究已表明癌症与PTEN基因多态性之间存在关联，但由PTEN多态性导致的乳腺癌（BC）化疗敏感性的潜在分子机制仍不清楚。本研究旨在探讨中国人群中顺式调控元件的PTEN多态性与BC化疗敏感性之间的潜在联系。该研究共纳入172例接受新辅助化疗的BC患者，其中化疗敏感病例104例，化疗耐药病例68例。结果显示rs786204926多态性与BC化疗敏感性之间存在显著关联。逻辑多元回归分析表明，年龄、淋巴结转移和rs786204926基因型是BC化疗耐药的危险因素。rs786204926的G等位基因更易增加BC化疗敏感性的风险。此外，使用Alamut Visual进行的分析表明，rs786204926的G等位基因倾向于产生一种新的PTEN突变体，该突变体在第4内含子中插入了18个碱基。虽然PTEN的转录水平在化疗敏感和化疗耐药样本中保持相似，但其蛋白水平发生了显著变化。有趣的是，两组之间新的PTEN突变体的转录和蛋白水平均存在显著差异。此外，我们发现该突变体与野生型PTEN相比更容易发生去磷酸化，通过PI3K-AKT信号通路导致化疗敏感性。这些发现表明，顺式调控元件多态性引起的新的PTEN突变体可能参与了BC化疗敏感性。
