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Breast Cancer Res Treat. 2015 Nov;154(1):23-32. doi: 10.1007/s10549-015-3589-7. Epub 2015 Oct 12.

FOXM1 cistrome predicts breast cancer metastatic outcome better than FOXM1 expression levels or tumor proliferation index.

Author information

1
Buck Institute for Research on Aging, 8001 Redwood Blvd., Novato, CA, 94945, USA.
2
Baskin School of Engineering, University of California, Santa Cruz, CA, USA.
3
NantOmics LLC, Santa Cruz, CA, USA.
4
Active Motif, Carlsbad, CA, USA.
5
Buck Institute for Research on Aging, 8001 Redwood Blvd., Novato, CA, 94945, USA. cbenz@buckinstitute.org.
6
Division of Hematology-Oncology, University of California, San Francisco, CA, USA. cbenz@buckinstitute.org.

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.

KEYWORDS:

Breast cancer FOXM1 genomic targets; FOXM1 ChIP-Seq; FOXM1 gene expression

PMID:
26456572
DOI:
10.1007/s10549-015-3589-7
[Indexed for MEDLINE]

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