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Title: Ionizing radiation predisposes non-malignant human mammaryepithelial cells to undergo TGF beta-induced epithelial to mesenchymaltransition

Abstract

Transforming growth factor {beta}1 (TGF{beta}) 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 TGF{beta}, activation in vivo. We now show that IR sensitizes human mammary epithelial cells (HMEC) to undergo TGF{beta}-mediated epithelial to mesenchymal transition (EMT). Non-malignant HMEC (MCF10A, HMT3522 S1 and 184v) were irradiated with 2 Gy shortly after attachment in monolayer culture, or treated with a low concentration of TGF{beta} (0.4 ng/ml), or double-treated. All double-treated (IR+TGF{beta}) HMEC underwent a morphological shift from cuboidal to spindle-shaped. This phenotype was accompanied by decreased expression of epithelial markers E-cadherin, {beta}-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{trademark}. Neither radiation nor TGF{beta} alone elicited EMT, even though IR increased chronic TGF{beta} signaling and activity. Gene expression profiling revealed that double treated cells exhibit a specific 10-gene signature associated with Erk/MAPK signaling. We hypothesized that IR-induced MAPK activation primes non-malignant HMEC to undergo TGF{beta}-mediated EMT. Consistent with this, Erk phosphorylation weremore » transiently induced by irradiation, persisted in irradiated cells treated with TGF{beta}, and treatment with U0126, a Mek inhibitor, blocked the EMT phenotype. Together, these data demonstrate that the interactions between radiation-induced signaling pathways elicit heritable phenotypes that could contribute to neoplastic progression.« less

Authors:
; ; ; ; ; ; ;
Publication Date:
Research Org.:
Ernest Orlando Lawrence Berkeley NationalLaboratory, Berkeley, CA (US)
Sponsoring Org.:
USDOE Director. Office of Science. Biological andEnvironmental Research
OSTI Identifier:
923349
Report Number(s):
LBNL-62603
Journal ID: ISSN 0008-5472; CNREA8; R&D Project: 443180; BnR: KP1104010; TRN: US200804%%1078
DOE Contract Number:  
DE-AC02-05CH11231
Resource Type:
Journal Article
Resource Relation:
Journal Name: Cancer Research; Journal Volume: 67; Related Information: Journal Publication Date: 09/15/2007
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ACTIN; CARCINOGENS; DRUGS; GENES; GROWTH FACTORS; IN VIVO; IONIZING RADIATIONS; IRRADIATION; MORPHOGENESIS; NEOPLASMS; PHENOTYPE; PHOSPHORYLATION; RADIATIONS; TUMOR PROMOTERS

Citation Formats

Andarawewa, Kumari L., Erickson, Anna C., Chou, William S., Costes, Sylvain, Gascard, Philippe, Mott, Joni D., Bissell, Mina J., and Barcellos-Hoff, Mary Helen. Ionizing radiation predisposes non-malignant human mammaryepithelial cells to undergo TGF beta-induced epithelial to mesenchymaltransition. United States: N. p., 2007. Web. doi:10.1158/0008-5472.CAN-07-1294.
Andarawewa, Kumari L., Erickson, Anna C., Chou, William S., Costes, Sylvain, Gascard, Philippe, Mott, Joni D., Bissell, Mina J., & Barcellos-Hoff, Mary Helen. Ionizing radiation predisposes non-malignant human mammaryepithelial cells to undergo TGF beta-induced epithelial to mesenchymaltransition. United States. doi:10.1158/0008-5472.CAN-07-1294.
Andarawewa, Kumari L., Erickson, Anna C., Chou, William S., Costes, Sylvain, Gascard, Philippe, Mott, Joni D., Bissell, Mina J., and Barcellos-Hoff, Mary Helen. Fri . "Ionizing radiation predisposes non-malignant human mammaryepithelial cells to undergo TGF beta-induced epithelial to mesenchymaltransition". United States. doi:10.1158/0008-5472.CAN-07-1294. https://www.osti.gov/servlets/purl/923349.
@article{osti_923349,
title = {Ionizing radiation predisposes non-malignant human mammaryepithelial cells to undergo TGF beta-induced epithelial to mesenchymaltransition},
author = {Andarawewa, Kumari L. and Erickson, Anna C. and Chou, William S. and Costes, Sylvain and Gascard, Philippe and Mott, Joni D. and Bissell, Mina J. and Barcellos-Hoff, Mary Helen},
abstractNote = {Transforming growth factor {beta}1 (TGF{beta}) 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 TGF{beta}, activation in vivo. We now show that IR sensitizes human mammary epithelial cells (HMEC) to undergo TGF{beta}-mediated epithelial to mesenchymal transition (EMT). Non-malignant HMEC (MCF10A, HMT3522 S1 and 184v) were irradiated with 2 Gy shortly after attachment in monolayer culture, or treated with a low concentration of TGF{beta} (0.4 ng/ml), or double-treated. All double-treated (IR+TGF{beta}) HMEC underwent a morphological shift from cuboidal to spindle-shaped. This phenotype was accompanied by decreased expression of epithelial markers E-cadherin, {beta}-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{trademark}. Neither radiation nor TGF{beta} alone elicited EMT, even though IR increased chronic TGF{beta} signaling and activity. Gene expression profiling revealed that double treated cells exhibit a specific 10-gene signature associated with Erk/MAPK signaling. We hypothesized that IR-induced MAPK activation primes non-malignant HMEC to undergo TGF{beta}-mediated EMT. Consistent with this, Erk phosphorylation were transiently induced by irradiation, persisted in irradiated cells treated with TGF{beta}, and treatment with U0126, a Mek inhibitor, blocked the EMT phenotype. Together, these data demonstrate that the interactions between radiation-induced signaling pathways elicit heritable phenotypes that could contribute to neoplastic progression.},
doi = {10.1158/0008-5472.CAN-07-1294},
journal = {Cancer Research},
number = ,
volume = 67,
place = {United States},
year = {Fri Apr 06 00:00:00 EDT 2007},
month = {Fri Apr 06 00:00:00 EDT 2007}
}