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 (+3 others)
2011 Cancer Cell  
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
more » ... hat TGFb mediated tumor acceleration. Tumor molecular signatures implicated TGFb, and genetically reducing TGFb abrogated the effect on latency. Surprisingly, tumors from irradiated hosts were predominantly estrogen receptor negative. This effect was TGFb 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.
doi:10.1016/j.ccr.2011.03.011 pmid:21575864 pmcid:PMC3110779 fatcat:g2a2t5exezh57pworj7mobbe74