TY - JOUR
T1 - Radiation Acts on the Microenvironment to Affect Breast Carcinogenesis by Distinct Mechanisms that Decrease Cancer Latency and Affect Tumor Type
AU - Nguyen, David H.
AU - Oketch-Rabah, Hellen A.
AU - Illa-Bochaca, Irineu
AU - Geyer, Felipe C.
AU - Reis-Filho, Jorge S.
AU - Mao, Jian Hua
AU - Ravani, Shraddha A.
AU - Zavadil, Jiri
AU - Borowsky, Alexander D.
AU - Jerry, D. Joseph
AU - Dunphy, Karen A.
AU - Seo, Jae Hong
AU - Haslam, Sandra
AU - Medina, Daniel
AU - Barcellos-Hoff, Mary Helen
N1 - Funding Information:
The authors thank Drs. P. Cowin, C. Allred, and P. Williams for helpful discussion, Dr. J. Paupert and Y. Huang for assistance with slide scoring, W. Chou, B. Chu, R. Chou, and B. Yang for technical assistance, and Y. Zhang of the NYU Cancer Institute Genomics Facility for generating the microarray data. This research was supported by a DOD-BCRP predoctoral fellowship to D.H.N., funds from Breakthrough Breast Cancer to F.C.G. and J.S.R.-F.; and grants to M.H.B.-H. from California Breast Cancer Research Program, the Department of Energy, Office of Biological and Environment Research Low Dose program, and the Breast Cancer and the Environment Research Centers grant number U01 ES/CA 012801 (M.H.B.-H.) and 012800 (S.H.) from the National Institute of Environmental Health Sciences and the National Cancer Institute of the National Institutes of Health. M.H.B.-H. designed research. H.A.O.-R., I.I.-B., S.A.R., S. H., F.C.G., J.S.R.-F., A.D.B., and D.H.N. performed research. D.J.J. and D.M. contributed reagents. D.H.N., I.I.-B., J.Z., J-H.M., and M.H.B.-H. analyzed data. D.H.N., D.M., and M.H.B.-H wrote the paper.
PY - 2011/5/17
Y1 - 2011/5/17
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=79955975612&partnerID=8YFLogxK
U2 - 10.1016/j.ccr.2011.03.011
DO - 10.1016/j.ccr.2011.03.011
M3 - Article
C2 - 21575864
AN - SCOPUS:79955975612
SN - 1535-6108
VL - 19
SP - 640
EP - 651
JO - Cancer Cell
JF - Cancer Cell
IS - 5
ER -
