title: Embryonic mammary signature subsets are activated in Brca1-/- and basal-like breast cancers.
abstract: BACKGROUND
  Cancer is often suggested to result from development gone awry. Links between normal embryonic development and cancer biology have been postulated, but no defined genetic basis has been established. We recently published the first transcriptomic analysis of embryonic mammary cell populations. Embryonic mammary epithelial cells are an immature progenitor cell population, lacking differentiation markers, which is reflected in their very distinct genetic profiles when compared with those of their postnatal descendents.
  
  
  METHODS
  We defined an embryonic mammary epithelial signature that incorporates the most highly expressed genes from embryonic mammary epithelium when compared with the postnatal mammary epithelial cells. We looked for activation of the embryonic mammary epithelial signature in mouse mammary tumors that formed in mice in which Brca1 had been conditionally deleted from the mammary epithelium and in human breast cancers to determine whether any genetic links exist between embryonic mammary cells and breast cancers.
  
  
  RESULTS
  Small subsets of the embryonic mammary epithelial signature were consistently activated in mouse Brca1-/- tumors and human basal-like breast cancers, which encoded predominantly transcriptional regulators, cell-cycle, and actin cytoskeleton components. Other embryonic gene subsets were found activated in non-basal-like tumor subtypes and repressed in basal-like tumors, including regulators of neuronal differentiation, transcription, and cell biosynthesis. Several embryonic genes showed significant upregulation in estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and/or grade 3 breast cancers. Among them, the transcription factor, SOX11, a progenitor cell and lineage regulator of nonmammary cell types, is found highly expressed in some Brca1-/- mammary tumors. By using RNA interference to silence SOX11 expression in breast cancer cells, we found evidence that SOX11 regulates breast cancer cell proliferation and cell survival.
  
  
  CONCLUSIONS
  Specific subsets of embryonic mammary genes, rather than the entire embryonic development transcriptomic program, are activated in tumorigenesis. Genes involved in embryonic mammary development are consistently upregulated in some breast cancers and warrant further investigation, potentially in drug-discovery research endeavors.
authors.forename: Marketa
authors.initials: M
authors.lastname: Zvelebil
authors.forename: Erik
authors.initials: E
authors.lastname: Oliemuller
authors.forename: Qiong
authors.initials: Q
authors.lastname: Gao
authors.forename: Olivia
authors.initials: O
authors.lastname: Wansbury
authors.forename: Alan
authors.initials: A
authors.lastname: Mackay
authors.forename: Howard
authors.initials: H
authors.lastname: Kendrick
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Smalley
authors.forename: Jorge S
authors.initials: JS
authors.lastname: Reis-Filho
authors.forename: Beatrice A
authors.initials: BA
authors.lastname: Howard
mesh_terms: D000818:Animals; D017209:Apoptosis; D019313:BRCA1 Protein / Q000502:physiology*; D015153:Blotting, Western; D001940:Breast / Q000378:metabolism* / Q000473:pathology; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002280:Basal Cell Carcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002453:Cell Cycle; D049109:Cell Proliferation; D004622:Embryo, Mammalian / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D053263:Gene Regulatory Networks; D006801:Humans; D007124:Immunoenzyme Techniques; D008321:Mammary Glands, Animal / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009361:Neoplasm Invasiveness; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055751:SOXC Transcription Factors / Q000037:antagonists & inhibitors / Q000502:physiology; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D019313:BRCA1 Protein; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D055751:SOXC Transcription Factors; C490793:Sox11 protein, mouse