Impact of p53 loss on reversal and recurrence of conditional Wnt-induced tumorigenesis

Edward Gunther, Susan E. Moody, George K. Belka, Kristina T. Hahn, Nathalie Innocent, Katherine D. Dugan, Robert D. Cardiff, Lewis A. Chodosh

Research output: Contribution to journalArticle

165 Citations (Scopus)

Abstract

Aberrant activation of Wnt signaling is oncogenic and has been implicated in a variety of human cancers. We have developed a doxycycline-inducible Wnt1 transgenic mouse model to determine the dependence of established mammary adenocarcinomas on continued Wnt signaling. Using this model we show that targeted down-regulation of the Wnt pathway results in the rapid disappearance of essentially all Wnt-initiated invasive primary tumors as well as pulmonary metastases. Tumor regression does not require p53 and occurs even in highly aneuploid tumors. However, despite the dependence of primary mammary tumors and metastases on continued Wnt signaling and the dispensability of p53 for tumor regression, we find that a substantial fraction of tumors progress to a Wnt-independent state and that p53 suppresses this process. Specifically, loss of one p53 allele dramatically facilitates the progression of mammary tumors to a Wnt1-independent state both by impairing the regression of primary tumors following doxycycline withdrawal and by promoting the recurrence of fully regressed tumors in the absence of doxycycline. Thus, although p53 itself is dispensable for tumor regression, it nevertheless plays a critical role in the suppression of tumor recurrence. Our findings demonstrate that although even advanced stages of epithelial malignancy remain dependent upon continued Wnt signaling for maintenance and growth, loss of p53 facilitates tumor escape and the acquisition of oncogene independence.

Original languageEnglish (US)
Pages (from-to)488-501
Number of pages14
JournalGenes and Development
Volume17
Issue number4
DOIs
StatePublished - Feb 15 2003

Fingerprint

Carcinogenesis
Recurrence
Neoplasms
Doxycycline
Breast Neoplasms
Tumor Escape
Neoplasm Metastasis
Wnt Signaling Pathway
Aneuploidy
Oncogenes
Transgenic Mice
Adenocarcinoma
Breast
Down-Regulation
Alleles
Maintenance
Lung
Growth

All Science Journal Classification (ASJC) codes

  • Genetics
  • Developmental Biology

Cite this

Gunther, E., Moody, S. E., Belka, G. K., Hahn, K. T., Innocent, N., Dugan, K. D., ... Chodosh, L. A. (2003). Impact of p53 loss on reversal and recurrence of conditional Wnt-induced tumorigenesis. Genes and Development, 17(4), 488-501. https://doi.org/10.1101/gad.1051603
Gunther, Edward ; Moody, Susan E. ; Belka, George K. ; Hahn, Kristina T. ; Innocent, Nathalie ; Dugan, Katherine D. ; Cardiff, Robert D. ; Chodosh, Lewis A. / Impact of p53 loss on reversal and recurrence of conditional Wnt-induced tumorigenesis. In: Genes and Development. 2003 ; Vol. 17, No. 4. pp. 488-501.
@article{c89799aeca1749ecb8f944cd6e1085a5,
title = "Impact of p53 loss on reversal and recurrence of conditional Wnt-induced tumorigenesis",
abstract = "Aberrant activation of Wnt signaling is oncogenic and has been implicated in a variety of human cancers. We have developed a doxycycline-inducible Wnt1 transgenic mouse model to determine the dependence of established mammary adenocarcinomas on continued Wnt signaling. Using this model we show that targeted down-regulation of the Wnt pathway results in the rapid disappearance of essentially all Wnt-initiated invasive primary tumors as well as pulmonary metastases. Tumor regression does not require p53 and occurs even in highly aneuploid tumors. However, despite the dependence of primary mammary tumors and metastases on continued Wnt signaling and the dispensability of p53 for tumor regression, we find that a substantial fraction of tumors progress to a Wnt-independent state and that p53 suppresses this process. Specifically, loss of one p53 allele dramatically facilitates the progression of mammary tumors to a Wnt1-independent state both by impairing the regression of primary tumors following doxycycline withdrawal and by promoting the recurrence of fully regressed tumors in the absence of doxycycline. Thus, although p53 itself is dispensable for tumor regression, it nevertheless plays a critical role in the suppression of tumor recurrence. Our findings demonstrate that although even advanced stages of epithelial malignancy remain dependent upon continued Wnt signaling for maintenance and growth, loss of p53 facilitates tumor escape and the acquisition of oncogene independence.",
author = "Edward Gunther and Moody, {Susan E.} and Belka, {George K.} and Hahn, {Kristina T.} and Nathalie Innocent and Dugan, {Katherine D.} and Cardiff, {Robert D.} and Chodosh, {Lewis A.}",
year = "2003",
month = "2",
day = "15",
doi = "10.1101/gad.1051603",
language = "English (US)",
volume = "17",
pages = "488--501",
journal = "Genes and Development",
issn = "0890-9369",
publisher = "Cold Spring Harbor Laboratory Press",
number = "4",

}

Gunther, E, Moody, SE, Belka, GK, Hahn, KT, Innocent, N, Dugan, KD, Cardiff, RD & Chodosh, LA 2003, 'Impact of p53 loss on reversal and recurrence of conditional Wnt-induced tumorigenesis', Genes and Development, vol. 17, no. 4, pp. 488-501. https://doi.org/10.1101/gad.1051603

Impact of p53 loss on reversal and recurrence of conditional Wnt-induced tumorigenesis. / Gunther, Edward; Moody, Susan E.; Belka, George K.; Hahn, Kristina T.; Innocent, Nathalie; Dugan, Katherine D.; Cardiff, Robert D.; Chodosh, Lewis A.

In: Genes and Development, Vol. 17, No. 4, 15.02.2003, p. 488-501.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Impact of p53 loss on reversal and recurrence of conditional Wnt-induced tumorigenesis

AU - Gunther, Edward

AU - Moody, Susan E.

AU - Belka, George K.

AU - Hahn, Kristina T.

AU - Innocent, Nathalie

AU - Dugan, Katherine D.

AU - Cardiff, Robert D.

AU - Chodosh, Lewis A.

PY - 2003/2/15

Y1 - 2003/2/15

N2 - Aberrant activation of Wnt signaling is oncogenic and has been implicated in a variety of human cancers. We have developed a doxycycline-inducible Wnt1 transgenic mouse model to determine the dependence of established mammary adenocarcinomas on continued Wnt signaling. Using this model we show that targeted down-regulation of the Wnt pathway results in the rapid disappearance of essentially all Wnt-initiated invasive primary tumors as well as pulmonary metastases. Tumor regression does not require p53 and occurs even in highly aneuploid tumors. However, despite the dependence of primary mammary tumors and metastases on continued Wnt signaling and the dispensability of p53 for tumor regression, we find that a substantial fraction of tumors progress to a Wnt-independent state and that p53 suppresses this process. Specifically, loss of one p53 allele dramatically facilitates the progression of mammary tumors to a Wnt1-independent state both by impairing the regression of primary tumors following doxycycline withdrawal and by promoting the recurrence of fully regressed tumors in the absence of doxycycline. Thus, although p53 itself is dispensable for tumor regression, it nevertheless plays a critical role in the suppression of tumor recurrence. Our findings demonstrate that although even advanced stages of epithelial malignancy remain dependent upon continued Wnt signaling for maintenance and growth, loss of p53 facilitates tumor escape and the acquisition of oncogene independence.

AB - Aberrant activation of Wnt signaling is oncogenic and has been implicated in a variety of human cancers. We have developed a doxycycline-inducible Wnt1 transgenic mouse model to determine the dependence of established mammary adenocarcinomas on continued Wnt signaling. Using this model we show that targeted down-regulation of the Wnt pathway results in the rapid disappearance of essentially all Wnt-initiated invasive primary tumors as well as pulmonary metastases. Tumor regression does not require p53 and occurs even in highly aneuploid tumors. However, despite the dependence of primary mammary tumors and metastases on continued Wnt signaling and the dispensability of p53 for tumor regression, we find that a substantial fraction of tumors progress to a Wnt-independent state and that p53 suppresses this process. Specifically, loss of one p53 allele dramatically facilitates the progression of mammary tumors to a Wnt1-independent state both by impairing the regression of primary tumors following doxycycline withdrawal and by promoting the recurrence of fully regressed tumors in the absence of doxycycline. Thus, although p53 itself is dispensable for tumor regression, it nevertheless plays a critical role in the suppression of tumor recurrence. Our findings demonstrate that although even advanced stages of epithelial malignancy remain dependent upon continued Wnt signaling for maintenance and growth, loss of p53 facilitates tumor escape and the acquisition of oncogene independence.

UR - http://www.scopus.com/inward/record.url?scp=0037442760&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0037442760&partnerID=8YFLogxK

U2 - 10.1101/gad.1051603

DO - 10.1101/gad.1051603

M3 - Article

VL - 17

SP - 488

EP - 501

JO - Genes and Development

JF - Genes and Development

SN - 0890-9369

IS - 4

ER -