Abstract
Approximately 70% of human breast cancers are estrogen receptor α (ERα)-positive, but the origins of ERα-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 ERα-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 ERα-positive and -negative tumors. p53 inactivation under a constitutive active WAPCrec in prepubertal/pubertal mice, but not under MMTVCre in adult mice, leads to the development of ERα-positive tumors, suggesting that target cells or developmental stages can determine ERα 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 ERα-positive and -negative breast tumors in mice.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 3525-3532 |
| Number of pages | 8 |
| Journal | Cancer Research |
| Volume | 64 |
| Issue number | 10 |
| DOIs | |
| State | Published - May 15 2004 |
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ASJC Scopus subject areas
- Oncology
- Cancer Research
Cite this
Somatic mutation of p53 leads to estrogen receptor α-positive and -negative mouse mammary tumors with high frequency of metastasis. / Lin, Suh Chin J.; Lee, Kuo Fen; Nikitin, Alexander Yu; Hilsenbeck, Susan G.; Cardiff, Robert; Li, Aihua; Kang, Keon Wook; Frank, Steven A.; Lee, Wen Hwa; Lee, Eva Y.H.P.
In: Cancer Research, Vol. 64, No. 10, 15.05.2004, p. 3525-3532.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Somatic mutation of p53 leads to estrogen receptor α-positive and -negative mouse mammary tumors with high frequency of metastasis
AU - Lin, Suh Chin J.
AU - Lee, Kuo Fen
AU - Nikitin, Alexander Yu
AU - Hilsenbeck, Susan G.
AU - Cardiff, Robert
AU - Li, Aihua
AU - Kang, Keon Wook
AU - Frank, Steven A.
AU - Lee, Wen Hwa
AU - Lee, Eva Y.H.P.
PY - 2004/5/15
Y1 - 2004/5/15
N2 - Approximately 70% of human breast cancers are estrogen receptor α (ERα)-positive, but the origins of ERα-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 ERα-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 ERα-positive and -negative tumors. p53 inactivation under a constitutive active WAPCrec in prepubertal/pubertal mice, but not under MMTVCre in adult mice, leads to the development of ERα-positive tumors, suggesting that target cells or developmental stages can determine ERα 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 ERα-positive and -negative breast tumors in mice.
AB - Approximately 70% of human breast cancers are estrogen receptor α (ERα)-positive, but the origins of ERα-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 ERα-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 ERα-positive and -negative tumors. p53 inactivation under a constitutive active WAPCrec in prepubertal/pubertal mice, but not under MMTVCre in adult mice, leads to the development of ERα-positive tumors, suggesting that target cells or developmental stages can determine ERα 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 ERα-positive and -negative breast tumors in mice.
UR - http://www.scopus.com/inward/record.url?scp=2442701845&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=2442701845&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-03-3524
DO - 10.1158/0008-5472.CAN-03-3524
M3 - Article
C2 - 15150107
AN - SCOPUS:2442701845
VL - 64
SP - 3525
EP - 3532
JO - Journal of Cancer Research
JF - Journal of Cancer Research
SN - 0099-7013
IS - 10
ER -