Division of Oncology, Washington University, St Louis, MO, USA.
Womens Cancer Research Center at UPMC Hillman Cancer Center and Magee Women's Research Institute, Pittsburgh, PA, USA.
Breast Cancer Res. 2024 Oct 30;26(1):149. doi: 10.1186/s13058-024-01900-y.
Invasive lobular breast cancer (ILC) is the most common special type of breast cancer and has unique clinicopathological and molecular hallmarks that differentiate it from the more common invasive carcinoma-no special type (NST). Despite these differences, ILC and NST are treated as a single entity and there is a lack of ILC-targeted therapies. To fill this gap, we sought to identify novel molecular alterations in ILC that could be exploited for targeted therapies.
Differential gene expression and Geneset Enrichment and Variation analyses were performed on RNA-seq data from three large public breast cancer databases-the Sweden Cancerome Analysis Network-Breast (SCAN-B; luminal A ILC N = 263, luminal A NST N = 1162), The Cancer Genome Atlas (TCGA; luminal A ILC N = 157, luminal A NST N = 307) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC; luminal A ILC N = 65, luminal A NST N = 533). Pathways enriched in overlapping differentially expressed genes from these datasets were clustered using Jaccard similarity to identify pathways enriched in ILC. The cAMP/PKA/CREB signaling was studied in ILC, ILC-like and NST cell lines and patient-derived organoids (PDOs) using forskolin, an activator of the pathway.
Clinicopathological features of patients with ILC and NST in SCAN-B were similar to prior population-based studies. There was a consistent pattern of up-regulation of cAMP/PKA/CREB related signaling in ILC compared to NST in SCAN-B, TCGA and METABRIC. Treatment with forskolin resulted in a greater increase in phospho-CREB in ILC cell lines and organoids than NST. CRISPR deletion of CDH1 in NST cell lines did not alter response of cells to forskolin as measured by phospho-CREB. Forskolin treatment caused growth inhibition in ILC and NST, with ILC cell lines being more sensitive to forskolin-mediated growth inhibition.
In three separate datasets, cAMP/PKA/CREB signaling was identified to be higher in ILC than NST. This in silico finding was validated in cell line and organoid models. Loss of CDH1 was not sufficient to mediate this phenotype. Future studies should investigate the mechanisms for differential cAMP/PKA/CREB signaling and the potential for therapeutic targeting in patients with ILC.
浸润性小叶乳腺癌（ILC）是最常见的特殊类型乳腺癌，具有独特的临床病理和分子特征，使其与更为常见的非特殊型浸润性癌（NST）不同。尽管存在这些差异，但 ILC 和 NST 仍被视为单一实体，并且缺乏针对 ILC 的靶向治疗方法。为了填补这一空白，我们试图确定 ILC 中可能用于靶向治疗的新的分子改变。
对三个大型公共乳腺癌数据库（瑞典癌症分析网络-乳腺（SCAN-B；luminal A ILC N=263，luminal A NST N=1162）、癌症基因组图谱（TCGA；luminal A ILC N=157，luminal A NST N=307）和乳腺癌国际分子分类协会（METABRIC；luminal A ILC N=65，luminal A NST N=533）中的 RNA-seq 数据进行差异基因表达和基因集富集及变异分析。使用 Jaccard 相似性对来自这些数据集的重叠差异表达基因进行聚类，以识别在 ILC 中富集的途径。使用 forskolin（该途径的激活剂）研究 ILC、ILC 样和 NST 细胞系以及患者来源的类器官（PDO）中的 cAMP/PKA/CREB 信号。
SCAN-B 中 ILC 和 NST 患者的临床病理特征与基于人群的先前研究相似。在 SCAN-B、TCGA 和 METABRIC 中，与 NST 相比，ILC 中 cAMP/PKA/CREB 相关信号的上调具有一致的模式。与 NST 相比，ILC 细胞系和类器官中用 forskolin处理后磷酸化 CREB 的增加更大。CRISPR 敲除 NST 细胞系中的 CDH1 并不会改变细胞对 forskolin的反应，如磷酸化 CREB 所示。福司可林处理导致 ILC 和 NST 生长抑制，其中 ILC 细胞系对福司可林介导的生长抑制更为敏感。
在三个独立的数据集，cAMP/PKA/CREB 信号在 ILC 中比 NST 中更高。这一计算机发现通过细胞系和类器官模型得到了验证。CDH1 的缺失不足以介导这种表型。未来的研究应探讨差异 cAMP/PKA/CREB 信号的机制以及在 ILC 患者中进行治疗靶向的潜力。
