title: MYC and PVT1 synergize to regulate RSPO1 levels in breast cancer.
abstract: Copy number gain of the 8q24 region including the v-myc avian myelocytomatosis viral oncogene homolog (MYC) oncogene has been observed in many different cancers and is associated with poor outcomes. While the role of MYC in tumor formation has been clearly delineated, we have recently shown that co-operation between adjacent long non-coding RNA plasmacytoma variant transcription 1 (PVT1) and MYC is necessary for tumor promotion. Chromosome engineered mice containing an increased copy of Myc-Pvt1 (Gain Myc-Pvt1) accelerates mammary tumors in MMTV-Neu mice, while single copy increase of each is not sufficient. In addition, mammary epithelium from the Gain Myc-Pvt1 mouse show precancerous phenotypes, notably increased DNA replication, elevated -H2AX 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 Myc-Pvt1 cooperation in mammary epithelial cells. In this extra view we show that an extra copy of both Myc and Pvt1 leads to increased levels of Rspo1, a crucial regulator of canonical β-catenin signaling required for female development. Human breast cancer tumors with high levels of MYC transcript have significantly more PVT1 transcript and RSPO1 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 MYC and PVT1, leading to increased premalignant features, and ultimately to tumor formation.
authors.affiliation: a Masonic Cancer Center, University of Minnesota , Minneapolis , MN , USA.
authors.forename: Aaron L
authors.initials: AL
authors.lastname: Sarver
authors.affiliation: b Computer Science Department, University of Minnesota , Minneapolis , MN , USA.
authors.forename: Collin D
authors.initials: CD
authors.lastname: Murray
authors.affiliation: a Masonic Cancer Center, University of Minnesota , Minneapolis , MN , USA.
authors.forename: Nuri A
authors.initials: NA
authors.lastname: Temiz
authors.affiliation: c Department of Genetics, Cell Biology and Development, University of Minnesota , Minneapolis , MN , USA.
authors.forename: Yuen-Yi
authors.initials: YY
authors.lastname: Tseng
authors.affiliation: a Masonic Cancer Center, University of Minnesota , Minneapolis , MN , USA.|c Department of Genetics, Cell Biology and Development, University of Minnesota , Minneapolis , MN , USA.
authors.forename: Anindya
authors.initials: A
authors.lastname: Bagchi
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics*; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002898:Chromosomes, Human, Pair 8; D016259:Genes, myc; D006801:Humans; D062085:RNA, Long Noncoding / Q000235:genetics; D051176:beta Catenin / Q000235:genetics
chemical_list: D062085:RNA, Long Noncoding; D051176:beta Catenin
keywords: cancer; copy number gain; MYC; PVT1; RSPO1