title: FOXM1 cistrome predicts breast cancer metastatic outcome better than FOXM1 expression levels or tumor proliferation index.
abstract: FOXM1 is a key transcription factor regulating cell cycle progression, DNA damage response, and a host of other hallmark cancer features, but the role of the FOXM1 cistrome in driving estrogen receptor-positive (ER+) versus estrogen receptor-negative (ER-) breast cancer clinical outcomes remains undefined. Chromatin immunoprecipitation sequencing (ChIP-Seq) coupled with RNA sequencing (RNA-Seq) analyses was used to identify FOXM1 target genes in breast cancer cells (MCF-7) where FOXM1 expression was either induced by cell proliferation or repressed by p53 upregulation. The prognostic performance of these FOXM1 target genes was assessed relative to FOXM transcript levels and a 61-gene proliferation score (PS) for their ability to dichotomize a pooled cohort of 683 adjuvant chemotherapy-naïve, node-negative breast cancer cases (447 ER+, 236 ER-). Differences in distant metastasis-free survival (DMFS) between the dichotomized expression groups were determined by Cox proportional hazard modeling. Proliferation-associated FOXM1 upregulation induced a set of 145 differentially bound and expressed genes (direct targets), and these demonstrated minimal overlap with differentially bound and expressed genes following FOXM1 repression by p53 upregulation. This proliferation-associated FOXM1 cistrome was not only better at significantly predicting metastatic outcome of ER+ breast cancers (HR: 2.8 (2.0-3.8), p = 8.13E-10), but was the only parameter trending toward significance in predicting ER- metastatic outcome (HR: 1.6 (0.9-2.9), p = 0.087). Our findings demonstrate that FOXM1 target genes are highly dependent on the cellular context in which FOXM1 expression is modulated, and a newly identified proliferation-associated FOXM1 cistromic signature best predicts breast cancer metastatic outcome.
authors.affiliation: Buck Institute for Research on Aging, 8001 Redwood Blvd., Novato, CA, 94945, USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Yau
authors.affiliation: Baskin School of Engineering, University of California, Santa Cruz, CA, USA.
authors.forename: Laurence
authors.initials: L
authors.lastname: Meyer
authors.affiliation: NantOmics LLC, Santa Cruz, CA, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Benz
authors.affiliation: NantOmics LLC, Santa Cruz, CA, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Vaske
authors.affiliation: Buck Institute for Research on Aging, 8001 Redwood Blvd., Novato, CA, 94945, USA.
authors.forename: Gary
authors.initials: G
authors.lastname: Scott
authors.affiliation: Active Motif, Carlsbad, CA, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Egan
authors.affiliation: Active Motif, Carlsbad, CA, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Labhart
authors.affiliation: Baskin School of Engineering, University of California, Santa Cruz, CA, USA.
authors.forename: Nader
authors.initials: N
authors.lastname: Pourmand
authors.affiliation: Buck Institute for Research on Aging, 8001 Redwood Blvd., Novato, CA, 94945, USA. cbenz@buckinstitute.org.|Division of Hematology-Oncology, University of California, San Francisco, CA, USA. cbenz@buckinstitute.org.
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Benz
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D049109:Cell Proliferation / Q000235:genetics; D018572:Disease-Free Survival; D047628:Estrogen Receptor alpha / Q000235:genetics; D005260:Female; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000096:biosynthesis / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D005796:Genes / Q000235:genetics*; D006801:Humans; D053208:Kaplan-Meier Estimate; D061986:MCF-7 Cells; D008940:Mitotic Index; D009363:Neoplasm Proteins / Q000096:biosynthesis; D011379:Prognosis
chemical_list: D047628:Estrogen Receptor alpha; C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D009363:Neoplasm Proteins
keywords: Breast cancer FOXM1 genomic targets; FOXM1 ChIP-Seq; FOXM1 gene expression