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Ionizing Radiation Predisposes Nonmalignant Human Mammary Epithelial Cells to Undergo Transforming Growth Factor ß–Induced Epithelial to Mesenchymal Transition

Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California

Requests for reprints: Mary Helen Barcellos-Hoff, Life Sciences Division, Building 977-225A, 1 Cyclotron Road, Berkeley, CA 94720. Phone: 510-486-6371; Fax: 510-486-5586; E-mail: MHBarcellos-Hoff{at}lbl.gov.

Transforming growth factor ß1 (TGFß) is a tumor suppressor during the initial stage of tumorigenesis, but it can switch to a tumor promoter during neoplastic progression. Ionizing radiation (IR), both a carcinogen and a therapeutic agent, induces TGFß activation in vivo. We now show that IR sensitizes human mammary epithelial cells (HMEC) to undergo TGFß-mediated epithelial to mesenchymal transition (EMT). Nonmalignant HMEC (MCF10A, HMT3522 S1, and 184v) were irradiated with 2 Gy shortly after attachment in monolayer culture or treated with a low concentration of TGFß (0.4 ng/mL) or double treated. All double-treated (IR + TGFß) HMEC underwent a morphologic shift from cuboidal to spindle shaped. This phenotype was accompanied by a decreased expression of epithelial markers E-cadherin, ß-catenin, and ZO-1, remodeling of the actin cytoskeleton, and increased expression of mesenchymal markers N-cadherin, fibronectin, and vimentin. Furthermore, double treatment increased cell motility, promoted invasion, and disrupted acinar morphogenesis of cells subsequently plated in Matrigel. Neither radiation nor TGFß alone elicited EMT, although IR increased chronic TGFß signaling and activity. Gene expression profiling revealed that double-treated cells exhibit a specific 10-gene signature associated with Erk/mitogen-activated protein kinase (MAPK) signaling. We hypothesized that IR-induced MAPK activation primes nonmalignant HMEC to undergo TGFß-mediated EMT. Consistent with this, Erk phosphorylation was transiently induced by irradiation and persisted in irradiated cells treated with TGFß, and treatment with U0126, a MAP/Erk kinase (MEK) inhibitor, blocked the EMT phenotype. Together, these data show that the interactions between radiation-induced signaling pathways elicit heritable phenotypes that could contribute to neoplastic progression. [Cancer Res 2007;67(18):8662–70]

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