Carcinogenesis:

Radiation carcinogenesis is classically understood in terms of DNA damage and the potential increase in oncogenic mutations.  Women who were treated with radiation therapy for childhood cancers have a breast cancer risk comparable to germline BRCA1 mutation carriers.  We study radiation in terms of its effects on cell phenotypes and interactions. We aim to identify when and how radiation alters signals and phenotypes and whether these contribute to the carcinogenic potential of radiation, as well as a better understanding of how normal tissues suppress carcinogenesis.

Based on our studies showing that radiation alters critical signaling and cell-cell interactions we developed a radiation chimera mammary to test this idea. In this model the mice are irradiated, then transplanted with unirradiated oncogenically primed mammary epithelial cells. Host irradiation accelerates tumorigenesis but surprisingly also affects the type of tumor, promoting those that are more aggressive. This model that unequivocally demonstrates that radiation effects on the microenvironment strongly promote carcinogenesis. 

The radiation-chimera mammary model has provided novel insight into the carcinogenic process that generates phenotypic and molecular breast cancer diversity via modulation of mammary stem cells, growth factors, and the immune response.   Remarkably, the expression profiles of  tumors arising in irradiated mice can be used to cluster cancer in irradiated humans, which supports the contention that this mechanism of action contributes to radiation-preceded cancer in humans and that similar processes may underlie the origin of specific types of human cancers. Notably host age at irradiation dramatically changes the type of tumor that subsequently arises and modifies the tumor microenvironment and immune infiltrate.  Our recent studies indicate that low dose radiation exposure impedes anti-tumor immunity resulting in more aggressive tumor growth.