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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.

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Buck Institute for Research on Aging, 8001 Redwood Blvd., Novato, CA, 94945, USA.
Baskin School of Engineering, University of California, Santa Cruz, CA, USA.
NantOmics LLC, Santa Cruz, CA, USA.
Active Motif, Carlsbad, CA, USA.
Buck Institute for Research on Aging, 8001 Redwood Blvd., Novato, CA, 94945, USA.
Division of Hematology-Oncology, University of California, San Francisco, CA, USA.


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.


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

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