title: Differential contextual responses of normal human breast epithelium to ionizing radiation in a mouse xenograft model.
abstract: Radiotherapy is a key treatment option for breast cancer, yet the molecular responses of normal human breast epithelial cells to ionizing radiation are unclear. A murine subcutaneous xenograft model was developed in which nonneoplastic human breast tissue was maintained with the preservation of normal tissue architecture, allowing us to study for the first time the radiation response of normal human breast tissue in situ. Ionizing radiation induced dose-dependent p53 stabilization and p53 phosphorylation, together with the induction of p21(CDKN1A) and apoptosis of normal breast epithelium. Although p53 was stabilized in both luminal and basal cells, induction of Ser392-phosphorylated p53 and p21 was higher in basal cells and varied along the length of the ductal system. Basal breast epithelial cells expressed ΔNp63, which was unchanged on irradiation. Although stromal responses themselves were minimal, the response of normal breast epithelium to ionizing radiation differed according to the stromal setting. We also demonstrated a dose-dependent induction of γ-H2AX foci in epithelial cells that was similarly dependent on the stromal environment and differed between basal and luminal epithelial cells. The intrinsic differences between human mammary cell types in response to in vivo irradiation are consistent with clinical observation that therapeutic ionizing radiation is associated with the development of basal-type breast carcinomas. Furthermore, there may be clinically important stromal-epithelial interactions that influence DNA damage responses in the normal breast. These findings demonstrate highly complex responses of normal human breast epithelium following ionizing radiation exposure and emphasize the importance of studying whole-tissue effects rather than single-cell systems.
authors.affiliation: Centre for Oncology and Molecular Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, UK. p.j.coates@dundee.ac.uk
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Coates
authors.forename: M Virginia C L
authors.initials: MV
authors.lastname: Appleyard
authors.forename: Karen
authors.initials: K
authors.lastname: Murray
authors.forename: Caroline
authors.initials: C
authors.lastname: Ackland
authors.forename: June
authors.initials: J
authors.lastname: Gardner
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Brown
authors.forename: Dougal J A
authors.initials: DJ
authors.lastname: Adamson
authors.forename: Lee B
authors.initials: LB
authors.lastname: Jordan
authors.forename: Colin A
authors.initials: CA
authors.lastname: Purdie
authors.forename: Alastair J
authors.initials: AJ
authors.lastname: Munro
authors.forename: Eric G
authors.initials: EG
authors.lastname: Wright
authors.forename: John A
authors.initials: JA
authors.lastname: Dewar
authors.forename: Alastair M
authors.initials: AM
authors.lastname: Thompson
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D001940:Breast / Q000378:metabolism / Q000528:radiation effects*; D053148:Caspase 3 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004307:Dose-Response Relationship, Radiation; D004789:Enzyme Activation / Q000528:radiation effects; D004847:Epithelial Cells / Q000378:metabolism / Q000528:radiation effects; D004848:Epithelium / Q000378:metabolism / Q000528:radiation effects*; D005260:Female; D006657:Histones / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D016513:Mice, SCID; D023421:Models, Animal; D010766:Phosphorylation / Q000528:radiation effects; D012694:Serine / Q000378:metabolism; D013997:Time Factors; D014183:Transplantation, Heterologous; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; C468783:H2AX protein, human; D006657:Histones; D016159:Tumor Suppressor Protein p53; D012694:Serine; D053148:Caspase 3