ABSTRACT
The FOXM1 transcription factor is an oncoprotein and a top biomarker of poor prognosis in human cancer. Overexpression and activation of FOXM1 is frequent in high-grade serous carcinoma (HGSC), the most common and lethal form of human ovarian cancer, and is linked to copy number gains at chromosome 12p13.33. We show that FOXM1 is co-amplified and co-expressed with RHNO1, a gene involved in the ATR-Chk1 signaling pathway that functions in the DNA replication stress response. We demonstrate that FOXM1 and RHNO1 are head-to-head (i.e., bidirectional) genes (BDG) regulated by a bidirectional promoter (BDP) (named F/R-BDP). FOXM1 and RHNO1 each promote oncogenic phenotypes in HGSC cells, including clonogenic growth, DNA homologous recombination repair, and poly-ADP ribosylase inhibitor resistance. FOXM1 and RHNO1 are one of the first examples of oncogenic BDG, and therapeutic targeting of FOXM1/RHNO1 BDG is a potential therapeutic approach for ovarian and other cancers.
Subject(s)
Carrier Proteins/genetics , Forkhead Box Protein M1/genetics , Gene Expression Regulation, Neoplastic , Neoplasms, Cystic, Mucinous, and Serous/genetics , Ovarian Neoplasms/genetics , Ataxia Telangiectasia Mutated Proteins/genetics , Ataxia Telangiectasia Mutated Proteins/metabolism , Carboplatin/pharmacology , Carrier Proteins/metabolism , Cell Line, Tumor , Cell Proliferation , Checkpoint Kinase 1/genetics , Checkpoint Kinase 1/metabolism , Databases, Genetic , Drug Resistance, Neoplasm , Female , Forkhead Box Protein M1/metabolism , Humans , Neoplasms, Cystic, Mucinous, and Serous/drug therapy , Neoplasms, Cystic, Mucinous, and Serous/metabolism , Neoplasms, Cystic, Mucinous, and Serous/pathology , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/metabolism , Ovarian Neoplasms/pathology , Poly(ADP-ribose) Polymerase Inhibitors/pharmacology , Promoter Regions, Genetic , Recombinational DNA Repair , Signal TransductionABSTRACT
FOXM1 is frequently overexpressed in cancer, but this has not been studied in a comprehensive manner. We utilized genotype-tissue expression (GTEx) normal and The Cancer Genome Atlas (TCGA) tumor data to define FOXM1 expression, including its isoforms, and to determine the genetic alterations that promote FOXM1 expression in cancer. Additionally, we used human fallopian tube epithelial (FTE) cells to dissect the role of Retinoblastoma (Rb)-E2F and Cyclin E1 in FOXM1 regulation, and a novel human embryonic kidney cell (HEK293T) CRISPR FOXM1 knockout model to define isoform-specific transcriptional programs. FOXM1 expression, at the mRNA and protein level, was significantly elevated in tumors with FOXM1 amplification, p53 inactivation, and Rb-E2F deregulation. FOXM1 expression was remarkably high in testicular germ cell tumors (TGCT), high-grade serous ovarian cancer (HGSC), and basal breast cancer (BBC). FOXM1 expression in cancer was associated with genomic instability, as measured using aneuploidy signatures. FTE models confirmed a role for Rb-E2F signaling in FOXM1 regulation and in particular identified Cyclin E1 as a novel inducer of FOXM1 expression. Among the three FOXM1 isoforms, FOXM1c showed the highest expression in normal and tumor tissues and cancer cell lines. The CRISPR knockout model demonstrated that FOXM1b and FOXM1c are transcriptionally active, while FOXM1a is not. Finally, we were unable to confirm the existence of a FOXM1 auto-regulatory loop. This study provides significant and novel information regarding the frequency, causes, and consequences of elevated FOXM1 expression in human cancer.
ABSTRACT
The National Institutes of Health and the National Science Foundation have made a compelling call to action not only to strengthen the pipeline of available STEM-trained talent, but in addition to foster students who are members of populations currently under-represented in science. Furthermore, the scientific community must not only increase the accessibility of STEM-related education, but also implement and test evidence-based practices. Presented here, we detail the proceedings of a hands-on, science-focused informal learning opportunity aimed at educating an underrepresented population in cancer biology. Fifteen undergraduate and graduate student volunteer instructors from the University of Nebraska at Omaha and the University of Nebraska Medical Center engaged with 89 high school students, mostly Native American, in an informal learning event called "Cancer Biology and You Day." Throughout the event, students completed two independent lessons focusing on breast cancer and skin cancer and demonstrated strong learning gains associated with the lessons as assessed by KWL charts. Exit surveys of the students indicated high levels of satisfaction with the event, and positive attitudes associated with considering a career in science/research were evident in survey responses. Overall, we report the event as a success and outline how similar experiences may be achieved.
