Pathways contributing to development of spontaneous mammary tumors in BALB/c-Trp53+/- mice

Haoheng Yan, Anneke C. Blackburn, S. Christine McLary, Luwei Tao, Amy L. Roberts, Elizabeth A. Xavier, Ellen S. Dickinson, Jae Hong Seo, Richard B. Arenas, Christopher N. Otis, Qing J. Cao, Rebecca G. Lawlor, Barbara A. Osborne, Frances S. Kittrell, Daniel Medina, D. Joseph Jerry

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11 Citations (Scopus)

Abstract

Mutation and loss of function in p53 are common features among human breast cancers. Here we use BALB/c-Trp53+/- mice as a model to examine the sequence of events leading to mammary tumors. Mammary gland proliferation rates were similar in both BALB/c-Trp53+/- mice and wild-type controls. In addition, sporadic mammary hyperplasias were rare in BALB/c-Trp53+/- mice and not detectably different from those of wild-type controls. Among the 28 mammary tumors collected from BALB/c-Trp53+/- mice, loss of heterozygosity for Trp53 was detected in more than 90% of invasive mammary tumors. Transplantation of Trp53+/- ductal hyperplasias also indicated an association between loss of the wild-type allele of Trp53 and progression to invasive carcinomas. Therefore, loss of p53 function seems to be a rate-limiting step in progression. Moreover, expression of biomarkers such as estrogen receptor κ, progesterone receptor, Her2/Neu, and activated Notch1 varied among mammary tumors, suggesting that multiple oncogenic lesions collaborate with loss of p53 function. Expression of biomarkers was retained when tumor fragments were transplanted to syngeneic hosts. Tumors expressing solely luminal or basal keratins were also observed (27 and 11%, respectively), but the largest class of tumors expressed both luminal and basal keratins (62%). Overall, this panel of transplantable tumors provides a resource for detailed evaluation of the cell lineages undergoing transformation and preclinical testing of therapeutic agents targeting a variety of oncogenic pathways including cancer stem cells.

Original languageEnglish
Pages (from-to)1421-1432
Number of pages12
JournalAmerican Journal of Pathology
Volume176
Issue number3
DOIs
Publication statusPublished - 2010 Mar

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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    Yan, H., Blackburn, A. C., McLary, S. C., Tao, L., Roberts, A. L., Xavier, E. A., Dickinson, E. S., Seo, J. H., Arenas, R. B., Otis, C. N., Cao, Q. J., Lawlor, R. G., Osborne, B. A., Kittrell, F. S., Medina, D., & Jerry, D. J. (2010). Pathways contributing to development of spontaneous mammary tumors in BALB/c-Trp53+/- mice. American Journal of Pathology, 176(3), 1421-1432. https://doi.org/10.2353/ajpath.2010.090438