<i>MYC</i> and <i>PVT1</i> synergize to regulate RSPO1 levels in breast cancer

<p>Copy number gain of the 8q24 region including the v-myc avian myelocytomatosis viral oncogene homolog (<i>MYC)</i> oncogene has been observed in many different cancers and is associated with poor outcomes. While the role of <i>MYC</i> in tumor formation has been clearly delineated, we have recently shown that co-operation between adjacent long non-coding RNA plasmacytoma variant transcription 1 (<i>PVT1)</i> and <i>MYC</i> is necessary for tumor promotion. Chromosome engineered mice containing an increased copy of <i>Myc-Pvt1</i> (Gain <i>Myc-Pvt1</i>) accelerates mammary tumors in <i>MMTV-Neu</i> mice, while single copy increase of each is not sufficient. In addition, mammary epithelium from the Gain <i>Myc-Pvt1</i> mouse show precancerous phenotypes, notably increased DNA replication, elevated -<i>H2AX</i> phosphorylation and increased ductal branching. In an attempt to capture the molecular signatures in pre-cancerous cells we utilized RNA sequencing to identify potential targets of supernumerary <i>Myc-Pvt1</i> cooperation in mammary epithelial cells. In this extra view we show that an extra copy of both <i>Myc</i> and <i>Pvt1</i> leads to increased levels of <i>Rspo1</i>, a crucial regulator of canonical β-catenin signaling required for female development. Human breast cancer tumors with high levels of <i>MYC</i> transcript have significantly more <i>PVT1</i> transcript and <i>RSPO1</i> transcript than tumors with low levels of MYC showing that the murine results are relevant to a subset of human tumors. Thus, this work identifies a key mechanism in precancerous and cancerous tissue by which a main player in female differentiation is transcriptionally activated by supernumerary <i>MYC</i> and <i>PVT1</i>, leading to increased premalignant features, and ultimately to tumor formation.</p>