title: Radiation acts on the microenvironment to affect breast carcinogenesis by distinct mechanisms that decrease cancer latency and affect tumor type.
abstract: Tissue microenvironment is an important determinant of carcinogenesis. We demonstrate that ionizing radiation, a known carcinogen, affects cancer frequency and characteristics by acting on the microenvironment. Using a mammary chimera model in which an irradiated host is transplanted with oncogenic Trp53 null epithelium, we show accelerated development of aggressive tumors whose molecular signatures were distinct from tumors arising in nonirradiated hosts. Molecular and genetic approaches show that TGFβ mediated tumor acceleration. Tumor molecular signatures implicated TGFβ, and genetically reducing TGFβ abrogated the effect on latency. Surprisingly, tumors from irradiated hosts were predominantly estrogen receptor negative. This effect was TGFβ independent and linked to mammary stem cell activity. Thus, the irradiated microenvironment affects latency and clinically relevant features of cancer through distinct and unexpected mechanisms.
authors.affiliation: Department of Radiation Oncology, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: David H
authors.initials: DH
authors.lastname: Nguyen
authors.forename: Hellen A
authors.initials: HA
authors.lastname: Oketch-Rabah
authors.forename: Irineu
authors.initials: I
authors.lastname: Illa-Bochaca
authors.forename: Felipe C
authors.initials: FC
authors.lastname: Geyer
authors.forename: Jorge S
authors.initials: JS
authors.lastname: Reis-Filho
authors.forename: Jian-Hua
authors.initials: JH
authors.lastname: Mao
authors.forename: Shraddha A
authors.initials: SA
authors.lastname: Ravani
authors.forename: Jiri
authors.initials: J
authors.lastname: Zavadil
authors.forename: Alexander D
authors.initials: AD
authors.lastname: Borowsky
authors.forename: D Joseph
authors.initials: DJ
authors.lastname: Jerry
authors.forename: Karen A
authors.initials: KA
authors.lastname: Dunphy
authors.forename: Jae Hong
authors.initials: JH
authors.lastname: Seo
authors.forename: Sandra
authors.initials: S
authors.lastname: Haslam
authors.forename: Daniel
authors.initials: D
authors.lastname: Medina
authors.forename: Mary Helen
authors.initials: MH
authors.lastname: Barcellos-Hoff
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000528:radiation effects*; D004307:Dose-Response Relationship, Radiation; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects* / Q000637:transplantation; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D008321:Mammary Glands, Animal / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects* / Q000637:transplantation; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009381:Neoplasms, Radiation-Induced / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011828:Radiation Chimera; D011930:Reaction Time; D011960:Receptors, Estrogen / Q000172:deficiency; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism; D047368:Tumor Burden; D059016:Tumor Microenvironment / Q000528:radiation effects*; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics; D014916:Whole-Body Irradiation
chemical_list: D011960:Receptors, Estrogen; C508961:Tgfb1 protein, mouse; D053773:Transforming Growth Factor beta1; D016159:Tumor Suppressor Protein p53