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This Article Accepted manuscript (PDF) All Versions of this Article: ERC-09-0038v1 16/2/381    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Lupien, M. Articles by Brown, M. Search for Related Content PubMed PubMed Citation Articles by Lupien, M. Articles by Brown, M.

M Lupien, Norris Cotton Cancer Center, Dartmouth Medical School, Lebanon, United States
M Brown, Dana-Farber Cancer Institute, Boston, 02115, United States

Correspondence: Myles Brown, Email: Myles_Brown{at}dfci.harvard.edu

Abstract

Alterations in transcription programs are a fundamental feature of cancer. Nuclear receptors, such as the estrogen (ER) and androgen receptors (AR), are central in this process as they can directly impact gene expression through interaction with the chromatin and subsequent association with coregulators and the transcriptional machinery. Unbiased genome-wide investigations have demonstrated the predominant recruitment of both ER and AR to distant (non-promoter) regulatory elements. Furthermore, these studies revealed a clear relationship between sites of transcription factor recruitment and gene regulation. Indeed, expression profiles from AR positive primary prostate tumors and cell lines directly relates to the AR cistrome in prostate cancer cells while the ER cistrome in breast cancer cells relates to expression profiles from ER-positive primary breast tumors. Additionally cell-type specific ER cistromes are linked to lineage-specific estrogen-induced expression profiles in different cell types, for example osteosarcoma and breast cancer cells. The pioneer factor FoxA1 plays a central role in AR and ER signaling. It is recruited in a lineage-specific manner translating the epigenetic signature consisting of mono- and dimethylated histone H3 on lysine 4 (H3K4me1/me2) into functional regulatory elements. Hence, through the interplay between the pioneer factor, namely FoxA1, and epigenetic events, the transcriptional potential of a given cell lineage is predefined. Since this directly impacts signaling through nuclear receptors, these discoveries should significantly impact the development of novel therapeutic strategies directed against multiple types of cancer.