Genetic mechanisms in Apc-mediated mammary tumorigenesis.
Many components of Wnt/beta-catenin signaling pathway also play critical roles in mammary tumor development, yet the role of the tumor suppressor gene APC (adenomatous polyposis coli) in breast oncongenesis is unclear. To better understand the role of Apc in mammary tumorigenesis, we introduced conditional Apc mutations specifically into two different mammary epithelial populations using K14-cre and WAP-cre transgenic mice that express Cre-recombinase in mammary progenitor cells and lactating luminal cells, respectively. Only the K14-cre-mediated Apc heterozygosity developed mammary adenocarcinomas demonstrating histological heterogeneity, suggesting the multilineage progenitor cell origin of these tumors. These tumors harbored truncation mutation in a defined region in the remaining wild-type allele of Apc that would retain some down-regulating activity of beta-catenin signaling. Activating mutations at codons 12 and 61 of either H-Ras or K-Ras were also found in a subset of these tumors. Expression profiles of acinar-type mammary tumors from K14-cre; Apc(CKO/+) mice showed luminal epithelial gene expression pattern, and clustering analysis demonstrated more correlation to MMTV-neu model than to MMTV-Wnt1. In contrast, neither WAP-cre-induced Apc heterozygous nor homozygous mutations resulted in predisposition to mammary tumorigenesis, although WAP-cre-mediated Apc deficiency resulted in severe squamous metaplasia of mammary glands. Collectively, our results suggest that not only the epithelial origin but also a certain Apc mutations are selected to achieve a specific level of beta-catenin signaling optimal for mammary tumor development and explain partially the colon- but not mammary-specific tumor development in patients that carry germline mutations in APC.
Kuraguchi
Mari
M
Harvard-Partners Center for Genetics and Genomics, Harvard Medical School, Boston, Massachusetts, USA. rkucherlapati@partners.org
Ohene-Baah
Nana Yaw
NY
Sonkin
Dmitriy
D
Bronson
Roderick Terry
RT
Kucherlapati
Raju
R
D011125:Adenomatous Polyposis Coli / Q000235:genetics*; D000818:Animals; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D017491:Genes, APC; D018095:Germ-Line Mutation; D019426:Integrases / Q000235:genetics / Q000378:metabolism; D053547:Keratin-14 / Q000235:genetics / Q000378:metabolism; D008321:Mammary Glands, Animal / Q000378:metabolism; D015674:Mammary Neoplasms, Animal / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008894:Milk Proteins / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics; D015398:Signal Transduction; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
D053547:Keratin-14; D008894:Milk Proteins; D051176:beta Catenin; C024471:whey acidic proteins; C045073:Cre recombinase; D019426:Integrases