The proapoptotic gene interferon regulatory factor-1 mediates the antiproliferative outcome of paired box 2 gene and tamoxifen

• Published in: Oncogene Vol. 39; no. 40; pp. 6300 - 6312
• Main Authors: Wang, Shixiong, Somisetty, Venkata S., Bai, Baoyan, Chernukhin, Igor, Niskanen, Henri, Kaikkonen, Minna U., Bellet, Meritxell, Carroll, Jason S., Hurtado, Antoni
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.10.2020; Nature Publishing Group
• Subjects: 13/2; 38/91; 631/67/1347; 692/53/2422; Antineoplastic Agents, Hormonal - pharmacology; Antineoplastic Agents, Hormonal - therapeutic use; Apoptosis; Apoptosis - drug effects; Apoptosis - genetics; Breast - pathology; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Care and treatment; Cell Biology; Cell death; Cell growth; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Proliferation - genetics; Cellular signal transduction; Chromatin Immunoprecipitation Sequencing; Development and progression; Drug Resistance, Neoplasm - genetics; ErbB-2 protein; Estrogen; Estrogen receptors; Estrogens; Estrogens - metabolism; Female; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Genes; Genetic aspects; Health aspects; Human Genetics; Humans; Interferon; Interferon regulatory factor; Interferon regulatory factor 1; Interferon Regulatory Factor-1 - genetics; Interferon Regulatory Factor-1 - metabolism; Internal Medicine; Medicine; Medicine & Public Health; Neoplasm Recurrence, Local - genetics; Oncology; Patient outcomes; Patients; Pax2 protein; PAX2 Transcription Factor - metabolism; Prognosis; Promoter Regions, Genetic - genetics; Receptor, ErbB-2 - metabolism; Receptors; Receptors, Estrogen - antagonists & inhibitors; Receptors, Estrogen - metabolism; Signal Transduction - drug effects; Tamoxifen; Tamoxifen - pharmacology; Tamoxifen - therapeutic use; Transcription factors; Transcriptional Activation - drug effects; Tumor cells; Tumors; Up-Regulation; Norway
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-020-01435-4

Tamoxifen is the most prescribed selective estrogen receptor (ER) modulator in patients with ER-positive breast cancers. Tamoxifen requires the transcription factor paired box 2 protein (PAX2) to repress the transcription of ERBB2/HER2. Now, we identified that PAX2 inhibits cell growth of ER+/HER2− tumor cells in a dose-dependent manner. Moreover, we have identified that cell growth inhibition can be achieved by expressing moderate levels of PAX2 in combination with tamoxifen treatment. Global run-on sequencing of cells overexpressing PAX2, when coupled with PAX2 ChIP-seq, identified common targets regulated by both PAX2 and tamoxifen. The data revealed that PAX2 can inhibit estrogen-induced gene transcription and this effect is enhanced by tamoxifen, suggesting that they converge on repression of the same targets. Moreover, PAX2 and tamoxifen have an additive effect and both induce coding genes and enhancer RNAs (eRNAs). PAX2–tamoxifen upregulated genes are also enriched with PAX2 eRNAs. The enrichment of eRNAs is associated with the highest expression of genes that positivity regulate apoptotic processes. In luminal tumors, the expression of a subset of these proapoptotic genes predicts good outcome and their expression are significantly reduced in tumors of patients with relapse to tamoxifen treatment. Mechanistically, PAX2 and tamoxifen coexert an antitumoral effect by maintaining high levels of transcription of tumor suppressors that promote cell death. The apoptotic effect is mediated in large part by the gene interferon regulatory factor 1. Altogether, we conclude that PAX2 contributes to better clinical outcome in tamoxifen treated ER-positive breast cancer patients by repressing estrogen signaling and inducing cell death related pathways.