Abstract
BackgroundProgesterone 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.MethodsThe 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.ResultsWe 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.ConclusionThe transcriptional targets identified in this study should facilitate the formulation or refinement of useful molecular descriptors for diagnosis, prognosis, and therapy of breast cancer.
Highlights
Progesterone receptor (PR) is expressed from a single gene as two isoforms, Progesterone receptor isoform A (PRA) and PRB
Transcriptional changes in PRA transgenic mammary glands To better understand the effects of PRA overexpression on breast cancer, we compared the expression profile in mammary glands of PRA transgenics with wild-type littermates using oligonucleotide microarray analysis
The expression signatures for wild-type and PRA transgenic mammary glands were strong enough to be recognized by unsupervised clustering (Fig. 1a)
Summary
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. Estrogen and progesterone signaling via their receptors play important roles in normal mammary gland development and in breast cancer progression [1, 2]. The two isoforms are expressed at similar levels in the breast, but the ratio can be altered in human breast tumors, with the PRA isoform predominating [6]. Preclinical studies with murine and human tumors and ex vivo human breast cancer tissue culture assays showed that antiprogestin responsiveness in breast cancer is determined by the PRA/PRB expression ratio, an inhibitory effect of the antiprogestin mifepristone is only obtained in tumors with higher levels of PRA than PRB [9, 10]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
