Discipline of Oncology, Department of Radiology and Oncology, Faculty of Medicine, University of São Paulo, São Paulo, SP, 01246-903, Brazil.
Laboratory of Molecular Genetics, Center for Translational Research in Oncology, Cancer Institute of São Paulo, São Paulo, SP, 01246-000, Brazil.
BMC Cancer. 2018 Jun 25;18(1):682. doi: 10.1186/s12885-018-4550-z.
Progesterone receptor (PR) is expressed from a single gene as two isoforms, PRA and PRB. In normal breast human tissue, PRA and PRB are expressed in equimolar ratios, but isoform ratio is altered during malignant progression, usually leading to high PRA:PRB ratios. We took advantage of a transgenic mouse model where PRA isoform is predominant (PRA transgenics) and identified the key transcriptional events and associated pathways underlying the preneoplastic phenotype in mammary glands of PRA transgenics as compared with normal wild-type littermates.
The transcriptomic profiles of PRA transgenics and wild-type mammary glands were generated using microarray technology. We identified differentially expressed genes and analyzed clustering, gene ontology (GO), gene set enrichment analysis (GSEA), and pathway profiles. We also performed comparisons with publicly available gene expression data sets of human breast cancer.
We identified a large number of differentially expressed genes which were mainly associated with metabolic pathways for the PRA transgenics phenotype while inflammation- related pathways were negatively correlated. Further, we determined a significant overlap of the pathways characterizing PRA transgenics and those in breast cancer subtypes Luminal A and Luminal B and identified novel putative biomarkers, such as PDHB and LAMB3.
The transcriptional targets identified in this study should facilitate the formulation or refinement of useful molecular descriptors for diagnosis, prognosis, and therapy of breast cancer.
孕激素受体（PR）由单个基因表达为两种异构体，即 PRA 和 PRB。在正常乳腺人类组织中，PRA 和 PRB 以等摩尔比例表达，但在恶性进展过程中，异构体比例发生改变，通常导致高 PRA:PRB 比值。我们利用一种 PRA 异构体占优势的转基因小鼠模型（PRA 转基因），并确定了与 PRA 转基因小鼠乳腺中癌前表型相关的关键转录事件和相关途径，与正常野生型同窝仔比较。
使用微阵列技术生成 PRA 转基因和野生型乳腺的转录组图谱。我们鉴定了差异表达基因，并分析了聚类、基因本体论（GO）、基因集富集分析（GSEA）和途径图谱。我们还与人类乳腺癌的公开基因表达数据集进行了比较。
我们鉴定了大量差异表达基因，这些基因主要与 PRA 转基因表型的代谢途径有关，而炎症相关途径呈负相关。此外，我们确定了表征 PRA 转基因的途径与乳腺癌亚型 Luminal A 和 Luminal B 的途径之间存在显著重叠，并鉴定了新的潜在生物标志物，如 PDHB 和 LAMB3。
本研究中鉴定的转录靶标应有助于制定或完善用于乳腺癌诊断、预后和治疗的有用分子描述符。
