Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Tōhoku, Japan.
Department of Pathology, National Hospital Organization, Sendai Medical Center, Sendai, Miyagi, Tōhoku, Japan.
Endocr Relat Cancer. 2023 Jun 22;30(7). doi: 10.1530/ERC-22-0204. Print 2023 Jul 1.
The presence of progesterone receptor (PR) and PR isoform B (PRB) in breast cancer is generally correlated with better clinical outcomes. Additionally, the significance of hormone-independent effects of PR/PRB correlated with better prognosis has been reported in non-small cell lung cancer (NSCLC). However, the detailed mechanism of that still remains unclear. In this study, we examined how microRNAs (miRNAs) could contribute to tumor inhibition via PR/PRB expression, in order to find miRNAs that have tumor-agnostic effects between breast cancer and NSCLC. We obtained miRNA data using human tissues of breast cancer and NSCLC from The Cancer Genome Atlas (TCGA) database and PCR array from NSCLC patients of our cohort. Subsequently, we examined the function of the miRNA through in vitro study using breast cancer cell lines. As a result, only let-7b expression was significantly correlated with PR expression in both cancers. Additionally, the expression of let-7b significantly inhibited cell proliferation by inducing PR and PRB expression in breast cancer cell lines. However, the positive correlation of let-7b and PRB required a mediated factor, E2 promoter binding factor 1 (E2F1), obtained from TCGA database analysis. In vitro experiments showed that let-7b significantly inhibited E2F1, and E2F1 significantly inhibited PRB. This study revealed that PRB inhibits the proliferation of breast cancer cells by the let-7b-E2F1 interaction. In addition, the immunohistochemical analysis in NSCLC was also consistent with these in vitro data. Our results could contribute to developing novel therapeutic strategies for patients with PR/PRB-positive cancer by targeting let-7b or PRB expression in breast cancer and possibly NSCLC.
孕激素受体（PR）和 PR 同工型 B（PRB）在乳腺癌中的存在通常与更好的临床结局相关。此外，在非小细胞肺癌（NSCLC）中已经报道了 PR/PRB 的激素非依赖性作用与更好的预后相关的意义。然而，其详细机制仍不清楚。在这项研究中，我们研究了 microRNAs（miRNAs）如何通过 PR/PRB 表达来促进肿瘤抑制，以寻找在乳腺癌和 NSCLC 之间具有肿瘤不可知效应的 miRNAs。我们从癌症基因组图谱（TCGA）数据库中获得了乳腺癌和 NSCLC 患者的组织 miRNA 数据和 NSCLC 患者的 PCR 阵列，随后通过体外研究使用乳腺癌细胞系检查了 miRNA 的功能。结果表明，仅 let-7b 的表达在两种癌症中均与 PR 表达显著相关。此外，let-7b 的表达通过诱导 PR 和 PRB 在乳腺癌细胞系中的表达显著抑制细胞增殖。然而，let-7b 和 PRB 的正相关需要一个中介因子，E2 启动子结合因子 1（E2F1），这是从 TCGA 数据库分析中获得的。体外实验表明 let-7b 显著抑制 E2F1，而 E2F1 显著抑制 PRB。这项研究表明，PRB 通过 let-7b-E2F1 相互作用抑制乳腺癌细胞的增殖。此外，在 NSCLC 中的免疫组织化学分析也与这些体外数据一致。我们的研究结果可能有助于通过针对乳腺癌和可能的 NSCLC 中的 let-7b 或 PRB 表达，为 PR/PRB 阳性癌症患者开发新的治疗策略。
