title: Epithelial and stromal microRNA signatures of columnar cell hyperplasia linking Let-7c to precancerous and cancerous breast cancer cell proliferation.
abstract: Columnar cell hyperplasia (CCH) is the earliest histologically identifiable breast lesion linked to cancer progression and is characterized by increased proliferation, decreased apoptosis and elevated oestrogen receptor α (ERα) expression. The mechanisms underlying the initiation of these lesions have not been clarified but might involve early and fundamental changes in cancer progression. MiRNAs are key regulators of several biological processes, acting by influencing the post-transcriptional regulation of numerous targets, thus making miRNAs potential candidates in cancer initiation. Here we have defined novel epithelial as well as stromal miRNA signatures from columnar cell hyperplasia lesions compared to normal terminal duct lobular units by using microdissection and miRNA microarrays. Let-7c were among the identified downregulated epithelial miRNAs and its functions were delineated in unique CCH derived cells and breast cancer cell line MCF-7 suggesting anti-proliferative traits potentially due to effects on Myb and ERα. MiR-132 was upregulated in the stroma surrounding CCH compared to stoma surrounding normal terminal duct lobular units (TDLUs), and overexpression of miR-132 in immortalized fibroblasts and in fibroblasts co-cultured with epithelial CCH cells caused substantial expression changes of genes involved in metabolism, DNA damage and cell motility. The miRNA signatures identified in CCH indicate early changes in the epithelial and stromal compartment of CCH and could represent early key alterations in breast cancer progression that potentially could be targeted in novel prevention or treatment schedules.
authors.affiliation: Center for Molecular Pathology, Skåne University Hospital, Department of Laboratory Medicine Malmö, Lund University, Malmö, Sweden; Breakthrough Breast Cancer Research Unit, Institute of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Paterson Institute for Cancer Research, The Christie National Health Service Foundation Trust, Manchester, United Kingdom; Sahlgrenska Cancer Center, Department of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Sofie
authors.initials: S
authors.lastname: Björner
authors.affiliation: Sahlgrenska Cancer Center, Department of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Fitzpatrick
authors.affiliation: Cancer Research UK Applied Computational Biology and Bioinformatics Group, Paterson Institute for Cancer Research, Manchester, United Kingdom.
authors.forename: Yaoyong
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri, United States of America.
authors.forename: Craig
authors.initials: C
authors.lastname: Allred
authors.affiliation: Breakthrough Breast Cancer Research Unit, Institute of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Paterson Institute for Cancer Research, The Christie National Health Service Foundation Trust, Manchester, United Kingdom.
authors.forename: Anthony
authors.initials: A
authors.lastname: Howell
authors.affiliation: Department of Plastic and Reconstructive Surgery, SUS Malmö, Institute of Clinical Sciences Malmö, Lund University, Malmö, Sweden.
authors.forename: Anita
authors.initials: A
authors.lastname: Ringberg
authors.affiliation: Department of Oncology, Skåne University Hospital, Institute of Clinical Sciences Lund, Lund University, Lund, Sweden.
authors.forename: Håkan
authors.initials: H
authors.lastname: Olsson
authors.affiliation: Cancer Research UK Applied Computational Biology and Bioinformatics Group, Paterson Institute for Cancer Research, Manchester, United Kingdom.
authors.forename: Crispin J
authors.initials: CJ
authors.lastname: Miller
authors.affiliation: Translational Cancer Research, Medicon Village, Department of Laboratory Medicine Malmö, Lund University, Lund, Sweden.
authors.forename: Håkan
authors.initials: H
authors.lastname: Axelson
authors.affiliation: Center for Molecular Pathology, Skåne University Hospital, Department of Laboratory Medicine Malmö, Lund University, Malmö, Sweden; Breakthrough Breast Cancer Research Unit, Institute of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Paterson Institute for Cancer Research, The Christie National Health Service Foundation Trust, Manchester, United Kingdom; Sahlgrenska Cancer Center, Department of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Göran
authors.initials: G
authors.lastname: Landberg
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology*; D049109:Cell Proliferation; D004847:Epithelial Cells / Q000378:metabolism*; D005260:Female; D006801:Humans; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D011230:Precancerous Conditions / Q000235:genetics / Q000473:pathology*; D020598:Proto-Oncogene Proteins c-myb / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D017154:Stromal Cells / Q000378:metabolism*
chemical_list: D035683:MicroRNAs; D020598:Proto-Oncogene Proteins c-myb; D011960:Receptors, Estrogen