Engineering Research Center of Cell & Therapeutic Antibody, MOE, School of Pharmacy, Shanghai Jiao Tong University, Building 6, Room 208, 800 Dongchuan road, Shanghai, 200240, China.
Jecho Laboratories, Inc, Frederick, MD, 21704, USA.
J Exp Clin Cancer Res. 2024 Jun 20;43(1):173. doi: 10.1186/s13046-024-03099-4.
Though tamoxifen achieves success in treating estrogen receptor α (ERα)-positive breast cancer, the followed development of tamoxifen resistance is a common challenge in clinic. Signals downstream of prolactin receptor (PRLR) could synergize with ERα in breast cancer progression. However, the potential effect of targeting PRL-PRLR axis combined with tamoxifen has not been thoroughly investigated.
High-throughput RNA-seq data obtained from TCGA, Metabric and GEO datasets were analyzed to explore PRLR expression in breast cancer cell and the association of PRLR expression with tamoxifen treatment. Exogenous or PRL overexpression cell models were employed to investigate the role of activated PRLR pathway in mediating tamoxifen insensitivity. Immunotoxin targeting PRLR (N8-PE24) was constructed with splicing-intein technique, and the efficacy of N8-PE24 against breast cancer was evaluated using in vitro and in vivo methods, including analysis of cells growth or apoptosis, 3D spheroids culture, and animal xenografts.
PRLR pathway activated by PRL could significantly decrease sensitivity of ERα-positive breast cancer cells to tamoxifen. Tamoxifen treatment upregulated transcription of PRLR and could induce significant accumulation of PRLR protein in breast cancer cells by alkalizing lysosomes. Meanwhile, tamoxifen-resistant MCF7 achieved by long-term tamoxifen pressure exhibited both upregulated transcription and protein level of PRLR. Immunotoxin N8-PE24 enhanced sensitivity of breast cancer cells to tamoxifen both in vitro and in vivo. In xenograft models, N8-PE24 significantly enhanced the efficacy of tamoxifen and paclitaxel when treating PRLR-positive triple-negative breast cancer.
PRL-PRLR axis potentially associates with tamoxifen insensitivity in ERα-positive breast cancer cells. N8-PE24 could inhibit cell growth of the breast cancers and promote drug sensitivity of PRLR-positive breast cancer cells to tamoxifen and paclitaxel. Our study provides a new perspective for targeting PRLR to treat breast cancer.
尽管他莫昔芬在治疗雌激素受体 α（ERα）阳性乳腺癌方面取得了成功，但随后出现的他莫昔芬耐药是临床中的常见挑战。催乳素受体（PRLR）下游信号可与乳腺癌进展中的 ERα 协同作用。然而，靶向 PRL-PRLR 轴联合他莫昔芬的潜在效果尚未得到彻底研究。
分析来自 TCGA、Metabric 和 GEO 数据集的高通量 RNA-seq 数据，以探讨 PRLR 在乳腺癌细胞中的表达以及 PRLR 表达与他莫昔芬治疗的关联。采用外源性或 PRL 过表达细胞模型研究激活的 PRLR 通路在介导他莫昔芬不敏感中的作用。采用拼接内含肽技术构建靶向 PRLR 的免疫毒素（N8-PE24），并通过体外和体内方法评估 N8-PE24 对乳腺癌的疗效，包括分析细胞生长或凋亡、3D 球体培养和动物异种移植。
PRL 激活的 PRLR 途径可显著降低 ERα 阳性乳腺癌细胞对他莫昔芬的敏感性。他莫昔芬治疗可上调 PRLR 的转录，并通过碱化溶酶体使乳腺癌细胞中 PRLR 蛋白大量积累。同时，长期他莫昔芬压力诱导的他莫昔芬耐药 MCF7 细胞表现出 PRLR 转录和蛋白水平的上调。免疫毒素 N8-PE24 可增强乳腺癌细胞对他莫昔芬的体外和体内敏感性。在异种移植模型中，N8-PE24 显著增强了 PRLR 阳性三阴性乳腺癌中他莫昔芬和紫杉醇的疗效。
PRL-PRLR 轴可能与 ERα 阳性乳腺癌细胞中的他莫昔芬不敏感有关。N8-PE24 可抑制乳腺癌细胞生长，并促进 PRLR 阳性乳腺癌细胞对他莫昔芬和紫杉醇的药物敏感性。我们的研究为靶向 PRLR 治疗乳腺癌提供了新视角。
