PARENT SESSION

Cell and Tissue Signaling

(PP203) Ionizing radiation predisposes human mammary epithelial cells to TGF induced epithelial to mesenchymal transition.

Andarawewa, Kumari ^*,1, Erickson, Anna ¹, Chou, William ¹, Bissell , Mina ¹, Barcellos-Hoff, Mary Helen ¹, ¹ Cancer biology, berkeley, CA, USA

ABSTRACT- Ionizing radiation (IR) is a known human breast carcinogen. Many aspects of the association between radiation and breast cancer have been elucidated in the past decades. Although the mutagenic capacity of IR is widely acknowledged as the basis for its action as a carcinogen, we and others have shown that IR can also induce growth factors and extracellular matrix remodeling. We have found that TGF is rapidly activated in irradiated tissues and wanted to identify its specific roles in how non–malignant human mammary epithelial cells (HMEC) respond to DNA damage and whether persistent phenotypes induced by radiation may promote its carcinogenic potential. To test this hypothesis we characterized the irradiated phenotype in non–malignant HMEC in presence or absence TGF We have demonstrated that irradiated single HMEC in presence of TGF can generate a persistent phenotype in daughter cells characterized by change in cell morphology, increased expression of mesenchymal markers, such as N–cadherin, fibronectin and vimentin, decreased expression of epithelial markers, E–cadherin and ZO–1, and increased cellular motility when compared to sham controls or following single treatments. These phenotypic changes are hallmarks of an epithelial to mesenchymal transition (EMT) event which is a signature of an aggressive type of tumor in vivo. The acquisition of the EMT phenotype by nonmalignant cells is a rare event in cell culture and this is the first report of an EMT event in HMEC. Thus, we suggest IR predisposes HMECs to TGF induced EMT and promote neoplastic progression.

Key words: Ionizing radiation, epithelial to mesenchymal transition, TGF, human mammary epithelial cells