Genome-wide mapping of FOXM1 binding reveals co-binding with estrogen receptor alpha in breast cancer cells.
BACKGROUND
The forkhead transcription factor FOXM1 is a key regulator of the cell cycle. It is frequently over-expressed in cancer and is emerging as an important therapeutic target. In breast cancer FOXM1 expression is linked with estrogen receptor (ERα) activity and resistance to endocrine therapies, with high levels correlated with poor prognosis. However, the precise role of FOXM1 in ER positive breast cancer is not yet fully understood.


RESULTS
The study utilizes chromatin immunoprecipitation followed by high-throughput sequencing to map FOXM1 binding in both ERα-positive and -negative breast cancer cell lines. The comparison between binding site distributions in the two cell lines uncovered a previously undescribed relationship between binding of FOXM1 and ERα. Further molecular analyses demonstrated that these two factors can bind simultaneously at genomic sites and furthermore that FOXM1 regulates the transcriptional activity of ERα via interaction with the coactivator CARM1. Inhibition of FOXM1 activity using the natural product thiostrepton revealed down-regulation of a set of FOXM1-regulated genes that are correlated with patient outcome in clinical breast cancer samples.


CONCLUSIONS
These findings reveal a novel role for FOXM1 in ERα transcriptional activity in breast cancer and uncover a FOXM1-regulated gene signature associated with ER-positive breast cancer patient prognosis.
Deborah A
DA
Sanders
Caryn S
CS
Ross-Innes
Dario
D
Beraldi
Jason S
JS
Carroll
Shankar
S
Balasubramanian
D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000235:genetics* / Q000378:metabolism; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human; D006801:Humans; D061986:MCF-7 Cells; D011485:Protein Binding; D011484:Protein-Arginine N-Methyltransferases / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D059467:Transcriptome
D047628:Estrogen Receptor alpha; C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D011484:Protein-Arginine N-Methyltransferases; C119966:coactivator-associated arginine methyltransferase 1