title: Irradiation of juvenile, but not adult, mammary gland increases stem cell self-renewal and estrogen receptor negative tumors.
abstract: Children exposed to ionizing radiation have a substantially greater breast cancer risk than adults; the mechanism for this strong age dependence is not known. Here we show that pubertal murine mammary glands exposed to sparsely or densely ionizing radiation exhibit enrichment of mammary stem cell and Notch pathways, increased mammary repopulating activity indicative of more stem cells, and propensity to develop estrogen receptor (ER) negative tumors thought to arise from stem cells. We developed a mammary lineage agent-based model (ABM) to evaluate cell inactivation, self-renewal, or dedifferentiation via epithelial-mesenchymal transition (EMT) as mechanisms by which radiation could increase stem cells. ABM rejected cell inactivation and predicted increased self-renewal would only affect juveniles while dedifferentiation could act in both juveniles and adults. To further test self-renewal versus dedifferentiation, we used the MCF10A human mammary epithelial cell line, which recapitulates ductal morphogenesis in humanized fat pads, undergoes EMT in response to radiation and transforming growth factor β (TGFβ) and contains rare stem-like cells that are Let-7c negative or express both basal and luminal cytokeratins. ABM simulation of population dynamics of double cytokeratin cells supported increased self-renewal in irradiated MCF10A treated with TGFβ. Radiation-induced Notch concomitant with TGFβ was necessary for increased self-renewal of Let-7c negative MCF10A cells but not for EMT, indicating that these are independent processes. Consistent with these data, irradiating adult mice did not increase mammary repopulating activity or ER-negative tumors. These studies suggest that irradiation during puberty transiently increases stem cell self-renewal, which increases susceptibility to developing ER-negative breast cancer.
authors.affiliation: Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley California, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Tang
authors.forename: Ignacio
authors.initials: I
authors.lastname: Fernandez-Garcia
authors.forename: Sangeetha
authors.initials: S
authors.lastname: Vijayakumar
authors.forename: Haydeliz
authors.initials: H
authors.lastname: Martinez-Ruis
authors.forename: Irineu
authors.initials: I
authors.lastname: Illa-Bochaca
authors.forename: David H
authors.initials: DH
authors.lastname: Nguyen
authors.forename: Jian-Hua
authors.initials: JH
authors.lastname: Mao
authors.forename: Sylvain V
authors.initials: SV
authors.lastname: Costes
authors.forename: Mary Helen
authors.initials: MH
authors.lastname: Barcellos-Hoff
mesh_terms: D000375:Aging / Q000473:pathology*; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002460:Cell Line; D019070:Cell Lineage; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D003198:Computer Simulation; D004307:Dose-Response Relationship, Radiation; D004847:Epithelial Cells / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects; D005260:Female; D006801:Humans; D008321:Mammary Glands, Animal / Q000473:pathology* / Q000528:radiation effects*; D015674:Mammary Neoplasms, Animal / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D009024:Morphogenesis / Q000187:drug effects / Q000528:radiation effects; D011839:Radiation, Ionizing; D011960:Receptors, Estrogen / Q000378:metabolism*; D051880:Receptors, Notch / Q000378:metabolism; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology* / Q000528:radiation effects; D016212:Transforming Growth Factor beta / Q000494:pharmacology
chemical_list: D015415:Biomarkers; D011960:Receptors, Estrogen; D051880:Receptors, Notch; D016212:Transforming Growth Factor beta
keywords: Breast cancer; Epithelial-mesenchymal transition; In silico modeling; Ionizing radiation; Mammary stem cell; Multiscale; Notch; Transforming growth factor β