Somatic mutation of p53 leads to estrogen receptor alpha-positive and -negative mouse mammary tumors with high frequency of metastasis.
Approximately 70% of human breast cancers are estrogen receptor alpha (ERalpha)-positive, but the origins of ERalpha-positive and -negative tumors remain unclear. Hormonal regulation of mammary gland development in mice is similar to that in humans; however, most mouse models produce only ERalpha-negative tumors. In addition, these mouse tumors metastasize at a low rate relative to human breast tumors. We report here that somatic mutations of p53 in mouse mammary epithelial cells using the Cre/loxP system leads to ERalpha-positive and -negative tumors. p53 inactivation under a constitutive active WAPCre(c) in prepubertal/pubertal mice, but not under MMTVCre in adult mice, leads to the development of ERalpha-positive tumors, suggesting that target cells or developmental stages can determine ERalpha status in mammary tumors. Importantly, these tumors have a high rate of metastasis. An inverse relationship between the number of targeted cells and median tumor latency was also observed. Median tumor latency reaches a plateau when targeted cell numbers exceed 20%, implying the existence of saturation kinetics for breast carcinogenesis. Genetic alterations commonly observed in human breast cancer including c-myc amplification and Her2/Neu/erbB2 activation were seen in these mouse tumors. Thus, this tumor system reproduces many important features of human breast cancer and provides tools for the study of the origins of ERalpha-positive and -negative breast tumors in mice.
Lin
Suh-Chin J
SC
Departments of Developmental and Cell Biology, University of California, Irvine, California 92697, USA.
Lee
Kuo-Fen
KF
Nikitin
Alexander Yu
AY
Hilsenbeck
Susan G
SG
Cardiff
Robert D
RD
Li
Aihua
A
Kang
Keon-Wook
KW
Frank
Steven A
SA
Lee
Wen-Hwa
WH
Lee
Eva Y-H P
EY
D000483:Alleles; D000818:Animals; D004195:Disease Models, Animal; D047628:Estrogen Receptor alpha; D005260:Female; D020868:Gene Silencing; D016158:Genes, p53 / Q000235:genetics*; D019426:Integrases / Q000235:genetics; D008325:Mammary Neoplasms, Experimental / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D009362:Neoplasm Metastasis; D011960:Receptors, Estrogen / Q000096:biosynthesis*; D014764:Viral Proteins / Q000235:genetics
D047628:Estrogen Receptor alpha; D011960:Receptors, Estrogen; D014764:Viral Proteins; C045073:Cre recombinase; D019426:Integrases