A cell-type-specific transcriptional network required for estrogen regulation of cyclin D1 and cell cycle progression in breast cancer.
Estrogen stimulates the proliferation of the most common type of human breast cancer that expresses estrogen receptor alpha (ERalpha) through the activation of the cyclin D1 (CCND1) oncogene. However, our knowledge of ERalpha transcriptional mechanisms remains limited. Hence, it is still elusive why ERalpha ectopically expressed in ER-negative breast cancer cells (BCC) is functional on ectopic reporter constructs but lacks activity on many endogenous target genes, including CCND1. Here, we show that estradiol (E2) stimulation of CCND1 expression in BCC depends on a novel cell-type-specific enhancer downstream from the CCND1 coding region, which is the primary ERalpha recruitment site in estrogen-responsive cells. The pioneer factor FoxA1 is specifically required for the active chromatin state of this enhancer and as such is crucial for both CCND1 expression and subsequent cell cycle progression. Interestingly, even in BCC, CCND1 levels and proliferation are tightly controlled by E2 through the establishment of a negative feedforward loop involving the induction of NFIC, a putative tumor suppressor capable of directly repressing CCND1 transcription. Taken together, our results reveal an estrogen-regulated combinatorial network including cell-specific cis- and trans-regulators of CCND1 expression where ERalpha collaborates with other transcription factors associated with the ER-positive breast cancer phenotype, including FoxA1 and NFIC.
Eeckhoute
Jérôme
J
Division of Molecular and Cellular Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
Carroll
Jason S
JS
Geistlinger
Timothy R
TR
Torres-Arzayus
Maria I
MI
Brown
Myles
M
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000235:genetics*; D004257:DNA Polymerase II / Q000378:metabolism; D004742:Enhancer Elements, Genetic; D004958:Estradiol / Q000378:metabolism* / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000235:genetics; D006801:Humans; D060588:LIM Domain Proteins; D008840:Microfilament Proteins / Q000235:genetics; D008954:Models, Biological; D051839:NFI Transcription Factors / Q000235:genetics; D009376:Neoplasms, Hormone-Dependent / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D014158:Transcription, Genetic / Q000187:drug effects
D048868:Adaptor Proteins, Signal Transducing; D047628:Estrogen Receptor alpha; C496499:FOXA1 protein, human; D051541:Hepatocyte Nuclear Factor 3-alpha; D060588:LIM Domain Proteins; D008840:Microfilament Proteins; D051839:NFI Transcription Factors; C497647:NFIC protein, human; C512485:PDLIM5 protein, human; D019938:Cyclin D1; D004958:Estradiol; D004257:DNA Polymerase II