title: Identification of an estrogen-regulated circadian mechanism necessary for breast acinar morphogenesis.
abstract: Altered estrogen receptor α (ERA) signaling and altered circadian rhythms are both features of breast cancer. By using a method to entrain circadian oscillations in human cultured cells, we recently reported that the expression of key clock genes oscillates in a circadian fashion in ERA-positive breast epithelial cells but not in breast cancer cells, regardless of their ERA status. Moreover, we reported that ERA mRNA oscillates in a circadian fashion in ERA-positive breast epithelial cells, but not in ERA-positive breast cancer cells. By using ERA-positive HME1 breast epithelial cells, which can be both entrained in vitro and can form mammary gland-like acinar structures in three-dimensional (3D) culture, first we identified a circuit encompassing ERA and an estrogen-regulated loop consisting of two circadian clock genes, PER2 and BMAL1. Further, we demonstrated that this estrogen-regulated circuit is necessary for breast epithelial acinar morphogenesis. Disruption of this circuit due to ERA-knockdown, negatively affects the estrogen-sustained circadian PER2-BMAL1 mechanism as well as the formation of 3D HME1 acini. Conversely, knockdown of either PER2 or BMAL1, by hampering the PER2-BMAL1 loop of the circadian clock, negatively affects ERA circadian oscillations and 3D breast acinar morphogenesis. To our knowledge, this study provides the first evidence of the implication of an ERA-circadian clock mechanism in the breast acinar morphogenetic process.
authors.affiliation: Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Stefano
authors.initials: S
authors.lastname: Rossetti
authors.forename: Francesca
authors.initials: F
authors.lastname: Corlazzoli
authors.forename: Alex
authors.initials: A
authors.lastname: Gregorski
authors.forename: Nurul Hidayah A
authors.initials: NH
authors.lastname: Azmi
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Sacchi
mesh_terms: D056930:ARNTL Transcription Factors / Q000235:genetics / Q000378:metabolism; D061354:Acinar Cells / Q000187:drug effects / Q000378:metabolism*; D001940:Breast / Q000166:cytology / Q000187:drug effects* / Q000254:growth & development*; D002940:Circadian Rhythm / Q000187:drug effects* / Q000235:genetics*; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D047628:Estrogen Receptor alpha / Q000378:metabolism; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D008954:Models, Biological; D009024:Morphogenesis / Q000187:drug effects* / Q000235:genetics; D056950:Period Circadian Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D056930:ARNTL Transcription Factors; C538960:BMAL1 protein, human; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D004967:Estrogens; C421902:PER2 protein, human; D056950:Period Circadian Proteins; D012333:RNA, Messenger