Radiation Acts on the Microenvironment to Affect Breast Carcinogenesis by Distinct Mechanisms that Decrease Cancer Latency and Affect Tumor Type

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

Research output: Contribution to journalArticle

103 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)640-651
Number of pages12
JournalCancer Cell
Volume19
Issue number5
DOIs
StatePublished - May 17 2011

ASJC Scopus subject areas

  • Cancer Research
  • Cell Biology
  • Oncology

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    Nguyen, D. H., Oketch-Rabah, H. A., Illa-Bochaca, I., Geyer, F. C., Reis-Filho, J. S., Mao, J. H., Ravani, S. A., Zavadil, J., Borowsky, A. D., Jerry, D. J., Dunphy, K. A., Seo, J. H., Haslam, S., Medina, D., & Barcellos-Hoff, M. H. (2011). Radiation Acts on the Microenvironment to Affect Breast Carcinogenesis by Distinct Mechanisms that Decrease Cancer Latency and Affect Tumor Type. Cancer Cell, 19(5), 640-651. https://doi.org/10.1016/j.ccr.2011.03.011