{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T16:18:54Z","timestamp":1781108334668,"version":"3.54.1"},"reference-count":19,"publisher":"National Academy of Sciences","issue":"15","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2007,4,10]]},"abstract":"<jats:p>\n                    Breast cancer risk is a polygenic trait. To identify breast cancer modifier alleles that have a high population frequency and low penetrance we used a comparative genomics approach. Quantitative trait loci (QTL) were initially identified by linkage analysis in a rat mammary carcinogenesis model followed by verification in congenic rats carrying the specific QTL allele under study. The\n                    <jats:italic>Mcs5a<\/jats:italic>\n                    locus was identified by fine-mapping\n                    <jats:italic>Mcs5<\/jats:italic>\n                    in a congenic model. Here we characterize the\n                    <jats:italic>Mcs5a<\/jats:italic>\n                    locus, which when homozygous for the Wky allele, reduces mammary cancer risk by 50%. The\n                    <jats:italic>Mcs5a<\/jats:italic>\n                    locus is a compound QTL with at least two noncoding interacting elements:\n                    <jats:italic>Mcs5a1<\/jats:italic>\n                    and\n                    <jats:italic>Mcs5a2<\/jats:italic>\n                    . The resistance phenotype is only observed in rats carrying at least one copy of the Wky allele of each element on the same chromosome.\n                    <jats:italic>Mcs5a1<\/jats:italic>\n                    is located within the ubiquitin ligase\n                    <jats:italic>Fbxo10<\/jats:italic>\n                    , whereas\n                    <jats:italic>Mcs5a2<\/jats:italic>\n                    includes the 5\u2032 portion of\n                    <jats:italic>Frmpd1<\/jats:italic>\n                    . Resistant congenic rats show a down-regulation of\n                    <jats:italic>Fbxo10<\/jats:italic>\n                    in the thymus and an up-regulation of\n                    <jats:italic>Frmpd1<\/jats:italic>\n                    in the spleen. The association of the\n                    <jats:italic>Mcs5a1<\/jats:italic>\n                    and\n                    <jats:italic>Mcs5a2<\/jats:italic>\n                    human orthologs with breast cancer was tested in two population-based breast cancer case-control studies (\u224812,000 women). The minor alleles of rs6476643 (\n                    <jats:italic>MCS5A1<\/jats:italic>\n                    ) and rs2182317 (\n                    <jats:italic>MCS5A2<\/jats:italic>\n                    ) were independently associated with breast cancer risk. The minor allele of rs6476643 increases risk, whereas the rs2182317 minor allele decreases risk. Both alleles have a high population frequency and a low penetrance toward breast cancer risk.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0701687104","type":"journal-article","created":{"date-parts":[[2007,4,2]],"date-time":"2007-04-02T21:04:22Z","timestamp":1175547862000},"page":"6299-6304","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":57,"title":["Rat\n                    <i>Mcs5a<\/i>\n                    is a compound quantitative trait locus with orthologous human loci that associate with breast cancer risk"],"prefix":"10.1073","volume":"104","author":[{"given":"David J.","family":"Samuelson","sequence":"first","affiliation":[{"name":"*McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin, Madison, WI 53706;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie E.","family":"Hesselson","sequence":"additional","affiliation":[{"name":"*McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin, Madison, WI 53706;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beth A.","family":"Aperavich","sequence":"additional","affiliation":[{"name":"*McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin, Madison, WI 53706;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunhong","family":"Zan","sequence":"additional","affiliation":[{"name":"*McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin, Madison, WI 53706;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jill D.","family":"Haag","sequence":"additional","affiliation":[{"name":"*McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin, Madison, WI 53706;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy","family":"Trentham-Dietz","sequence":"additional","affiliation":[{"name":"Department of Population Health Sciences, University of Wisconsin, Madison, WI 53726; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John M.","family":"Hampton","sequence":"additional","affiliation":[{"name":"Department of Population Health Sciences, University of Wisconsin, Madison, WI 53726; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bob","family":"Mau","sequence":"additional","affiliation":[{"name":"*McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin, Madison, WI 53706;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai-Shun","family":"Chen","sequence":"additional","affiliation":[{"name":"*McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin, Madison, WI 53706;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline","family":"Baynes","sequence":"additional","affiliation":[{"name":"Strangeways Research Laboratory, Cancer Research UK Department of Oncology, University of Cambridge, Worts Causeway, Cambridge CB1 8RN, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kay-Tee","family":"Khaw","sequence":"additional","affiliation":[{"name":"Strangeways Research Laboratory, Cancer Research UK Department of Oncology, University of Cambridge, Worts Causeway, Cambridge CB1 8RN, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Luben","sequence":"additional","affiliation":[{"name":"Strangeways Research Laboratory, Cancer Research UK Department of Oncology, University of Cambridge, Worts Causeway, Cambridge CB1 8RN, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Perkins","sequence":"additional","affiliation":[{"name":"Strangeways Research Laboratory, Cancer Research UK Department of Oncology, University of Cambridge, Worts Causeway, Cambridge CB1 8RN, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitul","family":"Shah","sequence":"additional","affiliation":[{"name":"Strangeways Research Laboratory, Cancer Research UK Department of Oncology, University of Cambridge, Worts Causeway, Cambridge CB1 8RN, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul D.","family":"Pharoah","sequence":"additional","affiliation":[{"name":"Strangeways Research Laboratory, Cancer Research UK Department of Oncology, University of Cambridge, Worts Causeway, Cambridge CB1 8RN, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alison M.","family":"Dunning","sequence":"additional","affiliation":[{"name":"Strangeways Research Laboratory, Cancer Research UK Department of Oncology, University of Cambridge, Worts Causeway, Cambridge CB1 8RN, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Doug F.","family":"Easton","sequence":"additional","affiliation":[{"name":"Strangeways Research Laboratory, Cancer Research UK Department of Oncology, University of Cambridge, Worts Causeway, Cambridge CB1 8RN, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce A.","family":"Ponder","sequence":"additional","affiliation":[{"name":"Strangeways Research Laboratory, Cancer Research UK Department of Oncology, University of Cambridge, Worts Causeway, Cambridge CB1 8RN, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael N.","family":"Gould","sequence":"additional","affiliation":[{"name":"*McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin, Madison, WI 53706;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2007,4,10]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0168-9525(01)02410-6"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1002\/gcc.20354"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng853"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1186\/bcr1083"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1023\/A:1026443305758"},{"key":"e_1_3_4_6_2","first-page":"50","volume":"113","author":"Russo J","year":"1983","unstructured":"J Russo, L Tait, IH Russo Am J Pathol 113, 50\u201366 (1983).","journal-title":"Am J Pathol"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1093\/genetics\/157.1.331"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-05-1498"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-9822(00)80020-2"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0968-0004(98)01237-7"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81307-0"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkj112"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1090005"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature03467"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1101\/gr.3437105"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1093\/carcin\/bgg112"},{"key":"e_1_3_4_17_2","first-page":"290","volume-title":"Practical Nonparametric Statistics","author":"Conover WJ","year":"1999","unstructured":"WJ Conover Practical Nonparametric StatisticsB Wiley, M O'Sullivan (Elm Street, 3rd Ed, New York), pp. 290 (1999).","edition":"3"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1186\/bcr1004"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1054\/bjoc.2000.1407"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.0701687104","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,25]],"date-time":"2022-04-25T23:06:20Z","timestamp":1650927980000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.0701687104"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2007,4,10]]},"references-count":19,"journal-issue":{"issue":"15","published-print":{"date-parts":[[2007,4,10]]}},"alternative-id":["10.1073\/pnas.0701687104"],"URL":"https:\/\/doi.org\/10.1073\/pnas.0701687104","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2007,4,10]]},"assertion":[{"value":"2006-10-31","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication 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