In vivo analysis of mammary and non-mammary tumorigenesis in MMTV-cyclin D1 transgenic mice deficient in p53

Yoshitaka Hosokawa, Alexandros Papanikolaou, Robert Cardiff, Katsuhiko Yoshimoto, Megan Bernstein, Timothy C. Wang, Emmett V. Schmidt, Andrew Arnold

Research output: Contribution to journalArticle

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Abstract

Overexpression of the cyclin D1 oncogene and inactivation of the p53 tumor suppressor have both been implicated in substantial proportions of sporadic human breast cancers. Transgenic mice with cyclin D1 overexpression targeted to mammary tissue by the MMTV enhancer-promoter have been shown to develop mammary cancers. To investigate the relationship between pathways driven by cyclin D1 overexpression and p53 loss during the development of breast cancers, we crossed MMTV-cyclin D1 mice with p53 heterozygous null (p53+/-) mice. In such crossed mice, cyclin D1-driven mammary neoplasia would need to be substantially accelerated by p53 loss in order for mammary tumors to develop prior to the expected onset of non-mammary tumors characteristic of the p53-deficient background alone. Instead, in mice heterozygous or homozygous for p53 deficiency and simultaneously carrying the MMTV-cyclin D1 transgene, only tumors typically found in p53-deficient mice developed and mammary tumors were not observed. Interestingly, MMTV-cyclin D1/p53+/- mice appeared to develop these non-mammary tumors more rapidly than p53+/- mice, and a majority of the sampled non-mammary tumors from MMTV-cyclin D1/p53+/- mice showed 'ectopic' expression of the MMTV-driven cyclin D1 transgene. Within the constraints of possible genetic background effects and limited sensitivity due to the early emergence of non-mammary tumors, these observations provide no evidence that inactivation of p53 confers a major additional selective advantage to mammary cells overexpressing cyclin D1 in this animal model of human breast cancer. Interestingly, the results do raise the possibility that p53 inactivation might complement or cooperate with cyclin D1 deregulation during the development of some types of non-mammary tumors.

Original languageEnglish (US)
Pages (from-to)471-478
Number of pages8
JournalTransgenic Research
Volume10
Issue number5
DOIs
StatePublished - Nov 9 2001

Fingerprint

Cyclin D1
cyclins
carcinogenesis
Transgenic Mice
breasts
Carcinogenesis
Breast
genetically modified organisms
mice
neoplasms
Breast Neoplasms
Neoplasms
breast neoplasms
inactivation
mammary neoplasms (animal)
Transgenes
transgenes
oncogenes
Oncogenes
genetic background

Keywords

  • Breast cancer
  • Cell cycle
  • Oncogenes
  • PRAD1
  • TP53
  • Tumor suppressor genes

ASJC Scopus subject areas

  • Biotechnology
  • Animal Science and Zoology
  • Genetics
  • Agronomy and Crop Science

Cite this

In vivo analysis of mammary and non-mammary tumorigenesis in MMTV-cyclin D1 transgenic mice deficient in p53. / Hosokawa, Yoshitaka; Papanikolaou, Alexandros; Cardiff, Robert; Yoshimoto, Katsuhiko; Bernstein, Megan; Wang, Timothy C.; Schmidt, Emmett V.; Arnold, Andrew.

In: Transgenic Research, Vol. 10, No. 5, 09.11.2001, p. 471-478.

Research output: Contribution to journalArticle

Hosokawa, Y, Papanikolaou, A, Cardiff, R, Yoshimoto, K, Bernstein, M, Wang, TC, Schmidt, EV & Arnold, A 2001, 'In vivo analysis of mammary and non-mammary tumorigenesis in MMTV-cyclin D1 transgenic mice deficient in p53', Transgenic Research, vol. 10, no. 5, pp. 471-478. https://doi.org/10.1023/A:1012064911751
Hosokawa, Yoshitaka ; Papanikolaou, Alexandros ; Cardiff, Robert ; Yoshimoto, Katsuhiko ; Bernstein, Megan ; Wang, Timothy C. ; Schmidt, Emmett V. ; Arnold, Andrew. / In vivo analysis of mammary and non-mammary tumorigenesis in MMTV-cyclin D1 transgenic mice deficient in p53. In: Transgenic Research. 2001 ; Vol. 10, No. 5. pp. 471-478.
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