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: David H Nguyen, Hellen A Oketch-Rabah, Irineu Illa-Bochaca, Felipe C Geyer, Jorge S Reis-Filho, Jian-Hua Mao, Shraddha A Ravani, Jiri Zavadil, Alexander D Borowsky, D Joseph Jerry, Karen A Dunphy, Jae Hong Seo, Sandra Haslam, Daniel Medina, Mary Helen Barcellos-Hoff
• Journal: Cancer cell (Cancer Cell) Vol. 19 Issue 5 Pg. 640-51 (May 17 2011) ISSN: 1878-3686 [Electronic] United States
• PMID: 21575864 (Publication Type: Comment, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2011 Elsevier Inc. All rights reserved.

Chemical References

• Receptors, Estrogen
• Tgfb1 protein, mouse
• Transforming Growth Factor beta1
• Tumor Suppressor Protein p53

Topics

• Animals
• Breast Neoplasms (etiology, genetics, metabolism, pathology)
• Cell Transformation, Neoplastic (radiation effects)
• Dose-Response Relationship, Radiation
• Epithelial Cells (metabolism, pathology, radiation effects, transplantation)
• Female
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• Gene Regulatory Networks
• Mammary Glands, Animal (metabolism, pathology, radiation effects, transplantation)
• Mice
• Mice, Inbred BALB C
• Mice, Knockout
• Neoplasms, Radiation-Induced (etiology, genetics, metabolism, pathology)
• Radiation Chimera
• Reaction Time
• Receptors, Estrogen (deficiency)
• Time Factors
• Transforming Growth Factor beta1 (genetics, metabolism)
• Tumor Burden
• Tumor Microenvironment (radiation effects)
• Tumor Suppressor Protein p53 (deficiency, genetics)
• Whole-Body Irradiation