Somatic mutation of p53 leads to estrogen receptor α-positive and -negative mouse mammary tumors with high frequency of metastasis

Suh Chin J. Lin, Kuo Fen Lee, Alexander Yu Nikitin, Susan G. Hilsenbeck, Robert Cardiff, Aihua Li, Keon Wook Kang, Steven A. Frank, Wen Hwa Lee, Eva Y.H.P. Lee

Research output: Contribution to journalArticle

89 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)3525-3532
Number of pages8
JournalCancer Research
Volume64
Issue number10
DOIs
StatePublished - May 15 2004

Fingerprint

Estrogen Receptors
Breast Neoplasms
Neoplasm Metastasis
Mutation
Neoplasms
Breast
Cell Count
Human Mammary Glands
Carcinogenesis
Epithelial Cells

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 journalArticle

Lin, SCJ, Lee, KF, Nikitin, AY, Hilsenbeck, SG, Cardiff, R, Li, A, Kang, KW, Frank, SA, Lee, WH & Lee, EYHP 2004, 'Somatic mutation of p53 leads to estrogen receptor α-positive and -negative mouse mammary tumors with high frequency of metastasis', Cancer Research, vol. 64, no. 10, pp. 3525-3532. https://doi.org/10.1158/0008-5472.CAN-03-3524
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. / Somatic mutation of p53 leads to estrogen receptor α-positive and -negative mouse mammary tumors with high frequency of metastasis. In: Cancer Research. 2004 ; Vol. 64, No. 10. pp. 3525-3532.
@article{d4bc9926438846e28996a96c35d60717,
title = "Somatic mutation of p53 leads to estrogen receptor α-positive and -negative mouse mammary tumors with high frequency of metastasis",
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.",
author = "Lin, {Suh Chin J.} and Lee, {Kuo Fen} and Nikitin, {Alexander Yu} and Hilsenbeck, {Susan G.} and Robert Cardiff and Aihua Li and Kang, {Keon Wook} and Frank, {Steven A.} and Lee, {Wen Hwa} and Lee, {Eva Y.H.P.}",
year = "2004",
month = "5",
day = "15",
doi = "10.1158/0008-5472.CAN-03-3524",
language = "English (US)",
volume = "64",
pages = "3525--3532",
journal = "Journal of Cancer Research",
issn = "0099-7013",
publisher = "American Association for Cancer Research Inc.",
number = "10",

}

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 -