{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,1]],"date-time":"2025-11-01T16:46:13Z","timestamp":1762015573864},"reference-count":37,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2015,3,9]],"date-time":"2015-03-09T00:00:00Z","timestamp":1425859200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2015,3,9]],"date-time":"2015-03-09T00:00:00Z","timestamp":1425859200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The interplay between host genetics, tumor microenvironment and environmental exposure in cancer susceptibility remains poorly understood. Here we assessed the genetic control of stromal mediation of mammary tumor susceptibility to low dose ionizing radiation (LDIR) using backcrossed F1 into BALB\/c (F1Bx) between cancer susceptible (BALB\/c) and resistant (SPRET\/EiJ) mouse strains. Tumor formation was evaluated after transplantation of non-irradiated <jats:italic>Trp53<\/jats:italic>-\/- BALB\/c mammary gland fragments into cleared fat pads of F1Bx hosts. Genome-wide linkage analysis revealed 2 genetic loci that constitute the baseline susceptibility via host microenvironment. However, once challenged with LDIR, we discovered 13 additional loci that were enriched for genes involved in cytokines, including TGF\u03b21 signaling. Surprisingly, LDIR-treated F1Bx cohort significantly reduced incidence of mammary tumors from <jats:italic>Trp53<\/jats:italic>-\/- fragments as well as prolonged tumor latency, compared to sham-treated controls. We demonstrated further that plasma levels of specific cytokines were significantly correlated with tumor latency. Using an <jats:italic>ex vivo<\/jats:italic> 3-D assay, we confirmed TGF\u03b21 as a strong candidate for reduced mammary invasion in SPRET\/EiJ, which could explain resistance of this strain to mammary cancer risk following LDIR. Our results open possible new avenues to understand mechanisms of genes operating via the stroma that affect cancer risk from external environmental exposures.<\/jats:p>","DOI":"10.1038\/srep08919","type":"journal-article","created":{"date-parts":[[2015,3,9]],"date-time":"2015-03-09T10:22:35Z","timestamp":1425896555000},"update-policy":"http:\/\/dx.doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Identification of genetic loci that control mammary tumor susceptibility through the host microenvironment"],"prefix":"10.1038","volume":"5","author":[{"given":"Pengju","family":"Zhang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alvin","family":"Lo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yurong","family":"Huang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ge","family":"Huang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guozhou","family":"Liang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joni","family":"Mott","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gary H.","family":"Karpen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eleanor A.","family":"Blakely","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mina J.","family":"Bissell","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mary Helen","family":"Barcellos-Hoff","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antoine M.","family":"Snijders","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jian-Hua","family":"Mao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2015,3,9]]},"reference":[{"key":"BFsrep08919_CR1","unstructured":"UNSCEAR Sources and effects of ionizing radiation. United Nations, New York, Vol 1 (2006)."},{"key":"BFsrep08919_CR2","doi-asserted-by":"publisher","first-page":"563","DOI":"10.1093\/jjco\/hys078","volume":"42","author":"K Suzuki","year":"2012","unstructured":"Suzuki, K. & Yamashita, S. Low-dose radiation exposure and carcinogenesis. Jpn J Clin Oncol 42, 563\u2013568 (2012).","journal-title":"Jpn J Clin Oncol"},{"key":"BFsrep08919_CR3","doi-asserted-by":"publisher","first-page":"596","DOI":"10.1038\/nrc2677","volume":"9","author":"L Mullenders","year":"2009","unstructured":"Mullenders, L., Atkinson, M., Paretzke, H., Sabatier, L. & Bouffler, S. Assessing cancer risks of low-dose radiation. Nat Rev Cancer 9, 596\u2013604 (2009).","journal-title":"Nat Rev Cancer"},{"key":"BFsrep08919_CR4","doi-asserted-by":"publisher","first-page":"501","DOI":"10.1667\/RR3306.1","volume":"179","author":"WF Morgan","year":"2013","unstructured":"Morgan, W. F. & Bair, W. J. Issues in low dose radiation biology: the controversy continues. A perspective. Radiat Res 179, 501\u2013510 (2013).","journal-title":"Radiat Res"},{"key":"BFsrep08919_CR5","doi-asserted-by":"publisher","first-page":"186","DOI":"10.1080\/10937404.2012.659136","volume":"15","author":"P Duport","year":"2012","unstructured":"Duport, P., Jiang, H., Shilnikova, N. S., Krewski, D. & Zielinski, J. M. Database of radiogenic cancer in experimental animals exposed to low doses of ionizing radiation. J Toxicol Environ Health B Crit Rev 15, 186\u2013209 (2012).","journal-title":"J Toxicol Environ Health B Crit Rev"},{"key":"BFsrep08919_CR6","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1586\/erc.10.184","volume":"9","author":"PK Nguyen","year":"2011","unstructured":"Nguyen, P. K. & Wu, J. C. Radiation exposure from imaging tests: is there an increased cancer risk? Expert Rev Cardiovasc Ther 9, 177\u2013183 (2011).","journal-title":"Expert Rev Cardiovasc Ther"},{"key":"BFsrep08919_CR7","doi-asserted-by":"publisher","first-page":"335","DOI":"10.1007\/978-1-4615-3940-7_16","volume":"53","author":"AA Donjacour","year":"1991","unstructured":"Donjacour, A. A. & Cunha, G. R. Stromal regulation of epithelial function. Cancer Treat Res 53, 335\u2013364 (1991).","journal-title":"Cancer Treat Res"},{"key":"BFsrep08919_CR8","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1038\/35094059","volume":"1","author":"MJ Bissell","year":"2001","unstructured":"Bissell, M. J. & Radisky, D. Putting tumours in context. Nat Rev Cancer 1, 46\u201354 (2001).","journal-title":"Nat Rev Cancer"},{"key":"BFsrep08919_CR9","doi-asserted-by":"publisher","first-page":"316","DOI":"10.1039\/c0ib00094a","volume":"3","author":"J Perez-Losada","year":"2011","unstructured":"Perez-Losada, J., Castellanos-Martin, A. & Mao, J. H. Cancer evolution and individual susceptibility. Integr Biol (Camb) 3, 316\u2013328 (2011).","journal-title":"Integr Biol (Camb)"},{"key":"BFsrep08919_CR10","doi-asserted-by":"publisher","first-page":"320","DOI":"10.1038\/nm.2328","volume":"17","author":"MJ Bissell","year":"2011","unstructured":"Bissell, M. J. & Hines, W. C. Why don't we get more cancer? A proposed role of the microenvironment in restraining cancer progression. Nat Med 17, 320\u2013329 (2011).","journal-title":"Nat Med"},{"key":"BFsrep08919_CR11","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1016\/j.cell.2010.03.015","volume":"141","author":"K Kessenbrock","year":"2010","unstructured":"Kessenbrock, K., Plaks, V. & Werb, Z. Matrix metalloproteinases: regulators of the tumor microenvironment. Cell 141, 52\u201367 (2010).","journal-title":"Cell"},{"key":"BFsrep08919_CR12","first-page":"1254","volume":"60","author":"MH Barcellos-Hoff","year":"2000","unstructured":"Barcellos-Hoff, M. H. & Ravani, S. A. Irradiated mammary gland stroma promotes the expression of tumorigenic potential by unirradiated epithelial cells. Cancer Res 60, 1254\u20131260 (2000).","journal-title":"Cancer Res"},{"key":"BFsrep08919_CR13","doi-asserted-by":"publisher","first-page":"640","DOI":"10.1016\/j.ccr.2011.03.011","volume":"19","author":"DH Nguyen","year":"2011","unstructured":"Nguyen, D. H. et al. Radiation acts on the microenvironment to affect breast carcinogenesis by distinct mechanisms that decrease cancer latency and affect tumor type. Cancer Cell 19, 640\u2013651 (2011).","journal-title":"Cancer Cell"},{"key":"BFsrep08919_CR14","doi-asserted-by":"publisher","first-page":"8304","DOI":"10.1158\/0008-5472.CAN-08-1212","volume":"68","author":"CA Maxwell","year":"2008","unstructured":"Maxwell, C. A. et al. Targeted and nontargeted effects of ionizing radiation that impact genomic instability. Cancer Res 68, 8304\u20138311 (2008).","journal-title":"Cancer Res"},{"key":"BFsrep08919_CR15","doi-asserted-by":"publisher","first-page":"867","DOI":"10.1038\/nrc1735","volume":"5","author":"MH Barcellos-Hoff","year":"2005","unstructured":"Barcellos-Hoff, M. H., Park, C. & Wright, E. G. Radiation and the microenvironment - tumorigenesis and therapy. Nat Rev Cancer 5, 867\u2013875 (2005).","journal-title":"Nat Rev Cancer"},{"key":"BFsrep08919_CR16","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1002\/path.4299","volume":"232","author":"D Mukherjee","year":"2014","unstructured":"Mukherjee, D., Coates, P. J., Lorimore, S. A. & Wright, E. G. Responses to ionizing radiation mediated by inflammatory mechanisms. J Pathol 232, 289\u2013299 (2014).","journal-title":"J Pathol"},{"key":"BFsrep08919_CR17","doi-asserted-by":"publisher","first-page":"2151","DOI":"10.1016\/S0002-9440(10)64853-5","volume":"157","author":"C Kuperwasser","year":"2000","unstructured":"Kuperwasser, C. et al. Development of spontaneous mammary tumors in BALB\/c p53 heterozygous mice. A model for Li-Fraumeni syndrome. Am J Pathol 157, 2151\u20132159 (2000).","journal-title":"Am J Pathol"},{"key":"BFsrep08919_CR18","first-page":"2364","volume":"63","author":"AC Blackburn","year":"2003","unstructured":"Blackburn, A. C. et al. BALB\/c alleles for Prkdc and Cdkn2a interact to modify tumor susceptibility in Trp53+\/- mice. Cancer Res 63, 2364\u20132368 (2003).","journal-title":"Cancer Res"},{"key":"BFsrep08919_CR19","first-page":"4342","volume":"60","author":"R Okayasu","year":"2000","unstructured":"Okayasu, R. et al. A deficiency in DNA repair and DNA-PKcs expression in the radiosensitive BALB\/c mouse. Cancer Res 60, 4342\u20134345 (2000).","journal-title":"Cancer Res"},{"key":"BFsrep08919_CR20","doi-asserted-by":"publisher","first-page":"403","DOI":"10.1038\/ng1220","volume":"34","author":"A Ewart-Toland","year":"2003","unstructured":"Ewart-Toland, A. et al. Identification of Stk6\/STK15 as a candidate low-penetrance tumor-susceptibility gene in mouse and human. Nat Genet 34, 403\u2013412 (2003).","journal-title":"Nat Genet"},{"key":"BFsrep08919_CR21","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1016\/S0959-437X(03)00005-4","volume":"13","author":"JH Mao","year":"2003","unstructured":"Mao, J. H. & Balmain, A. Genomic approaches to identification of tumour-susceptibility genes using mouse models. Curr Opin Genet Dev 13, 14\u201319 (2003).","journal-title":"Curr Opin Genet Dev"},{"key":"BFsrep08919_CR22","doi-asserted-by":"publisher","first-page":"775","DOI":"10.1038\/nature03155","volume":"432","author":"JH Mao","year":"2004","unstructured":"Mao, J. H. et al. Fbxw7\/Cdc4 is a p53-dependent, haploinsufficient tumour suppressor gene. Nature 432, 775\u2013779 (2004).","journal-title":"Nature"},{"key":"BFsrep08919_CR23","doi-asserted-by":"publisher","first-page":"926","DOI":"10.1038\/ng1836","volume":"38","author":"MD To","year":"2006","unstructured":"To, M. D. et al. A functional switch from lung cancer resistance to susceptibility at the Pas1 locus in Kras2LA2 mice. Nat Genet 38, 926\u2013930 (2006).","journal-title":"Nat Genet"},{"key":"BFsrep08919_CR24","doi-asserted-by":"publisher","first-page":"298","DOI":"10.1126\/science.1131000","volume":"314","author":"CM Nelson","year":"2006","unstructured":"Nelson, C. M., Vanduijn, M. M., Inman, J. L., Fletcher, D. A. & Bissell, M. J. Tissue geometry determines sites of mammary branching morphogenesis in organotypic cultures. Science 314, 298\u2013300 (2006).","journal-title":"Science"},{"key":"BFsrep08919_CR25","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1007\/s10911-012-9251-7","volume":"17","author":"AT Lo","year":"2012","unstructured":"Lo, A. T., Mori, H., Mott, J. & Bissell, M. J. Constructing three-dimensional models to study mammary gland branching morphogenesis and functional differentiation. J Mammary Gland Biol Neoplasia 17, 103\u2013110 (2012).","journal-title":"J Mammary Gland Biol Neoplasia"},{"key":"BFsrep08919_CR26","doi-asserted-by":"publisher","first-page":"721","DOI":"10.1038\/nrg1157","volume":"4","author":"P Demant","year":"2003","unstructured":"Demant, P. Cancer susceptibility in the mouse: genetics, biology and implications for human cancer. Nat Rev Genet 4, 721\u2013734 (2003).","journal-title":"Nat Rev Genet"},{"key":"BFsrep08919_CR27","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1002\/ijc.2910550217","volume":"55","author":"B Tartakovsky","year":"1993","unstructured":"Tartakovsky, B., Goldstein, O., Krautghamer, R. & Haran-Ghera, N. Low doses of radiation induce systemic production of cytokines: possible contribution to leukemogenesis. Int J Cancer 55, 269\u2013274 (1993).","journal-title":"Int J Cancer"},{"key":"BFsrep08919_CR28","first-page":"1095","volume":"9","author":"A Peled","year":"1995","unstructured":"Peled, A., Tzehoval, E. & Haran-Ghera, N. Role of cytokines in termination of the B cell lymphoma dormant state in AKR mice. Leukemia 9, 1095\u20131101 (1995).","journal-title":"Leukemia"},{"key":"BFsrep08919_CR29","doi-asserted-by":"crossref","first-page":"2537","DOI":"10.1182\/blood.V89.7.2537","volume":"89","author":"N Haran-Ghera","year":"1997","unstructured":"Haran-Ghera, N. et al. Increased circulating colony-stimulating factor-1 (CSF-1) in SJL\/J mice with radiation-induced acute myeloid leukemia (AML) is associated with autocrine regulation of AML cells by CSF-1. Blood 89, 2537\u20132545 (1997).","journal-title":"Blood"},{"key":"BFsrep08919_CR30","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1007\/s10911-011-9220-6","volume":"16","author":"MH Barcellos-Hoff","year":"2011","unstructured":"Barcellos-Hoff, M. H. TGFbeta biology in breast: 15 years on. J Mammary Gland Biol Neoplasia 16, 65\u201366 (2011).","journal-title":"J Mammary Gland Biol Neoplasia"},{"key":"BFsrep08919_CR31","doi-asserted-by":"publisher","first-page":"a003277","DOI":"10.1101\/cshperspect.a003277","volume":"3","author":"H Moses","year":"2011","unstructured":"Moses, H. & Barcellos-Hoff, M. H. TGF-beta biology in mammary development and breast cancer. Cold Spring Harb Perspect Biol 3, a003277 (2011).","journal-title":"Cold Spring Harb Perspect Biol"},{"key":"BFsrep08919_CR32","doi-asserted-by":"publisher","first-page":"531","DOI":"10.1016\/S0092-8674(00)80127-0","volume":"86","author":"W Cui","year":"1996","unstructured":"Cui, W. et al. TGFbeta1 inhibits the formation of benign skin tumors, but enhances progression to invasive spindle carcinomas in transgenic mice. Cell 86, 531\u2013542 (1996).","journal-title":"Cell"},{"key":"BFsrep08919_CR33","doi-asserted-by":"publisher","first-page":"8621","DOI":"10.1073\/pnas.1633291100","volume":"100","author":"AB Roberts","year":"2003","unstructured":"Roberts, A. B. & Wakefield, L. M. The two faces of transforming growth factor beta in carcinogenesis. Proc Natl Acad Sci U S A 100, 8621\u20138623 (2003).","journal-title":"Proc Natl Acad Sci U S A"},{"key":"BFsrep08919_CR34","first-page":"259","volume":"20","author":"MB Sporn","year":"1989","unstructured":"Sporn, M. B., Roberts, A. B., Wakefield, L. M., Glick, A. B. & Danielpour, D. Transforming growth factor-beta and suppression of carcinogenesis. Princess Takamatsu Symp 20, 259\u2013266 (1989).","journal-title":"Princess Takamatsu Symp"},{"key":"BFsrep08919_CR35","first-page":"133","volume":"391","author":"LM Wakefield","year":"1995","unstructured":"Wakefield, L. M. et al. Transforming growth factor-beta s in mammary tumorigenesis: promoters or antipromoters? Prog Clin Biol Res 391, 133\u2013148 (1995).","journal-title":"Prog Clin Biol Res"},{"key":"BFsrep08919_CR36","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1016\/S0959-437X(01)00259-3","volume":"12","author":"LM Wakefield","year":"2002","unstructured":"Wakefield, L. M. & Roberts, A. B. TGF-beta signaling: positive and negative effects on tumorigenesis. Curr Opin Genet Dev 12, 22\u201329 (2002).","journal-title":"Curr Opin Genet Dev"},{"key":"BFsrep08919_CR37","doi-asserted-by":"publisher","first-page":"12564","DOI":"10.1073\/pnas.0914191107","volume":"107","author":"A Burgess","year":"2010","unstructured":"Burgess, A. et al. Loss of human Greatwall results in G2 arrest and multiple mitotic defects due to deregulation of the cyclin B-Cdc2\/PP2A balance. Proc Natl Acad Sci U S A 107, 12564\u201312569 (2010).","journal-title":"Proc Natl Acad Sci U S A"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/srep08919","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep08919.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep08919.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,5]],"date-time":"2023-01-05T16:33:25Z","timestamp":1672936405000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/srep08919"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,3,9]]},"references-count":37,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2015,8,14]]}},"alternative-id":["BFsrep08919"],"URL":"https:\/\/doi.org\/10.1038\/srep08919","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,3,9]]},"assertion":[{"value":"15 October 2014","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 January 2015","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 March 2015","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing financial interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"8919"}}