Targeted inactivation of p27kip1 is sufficient for large and small intestinal tumorigenesis in the mouse, which can be augmented by a Western-style high-risk diet

WanCai Yang, Laura Bancroft, Courtney Nicholas, Ioana Lozonschi, Leonard H. Augenlicht

Research output: Contribution to journalArticle

48 Citations (Scopus)

Abstract

Mice with a targeted inactivation of both alleles of the cyclin-dependent kinase inhibitor p27kip1 developed both small and large intestinal adenomas when fed a control AIN-76A diet. A Western-style diet that is high in fat and phosphate and low in calcium and vitamin D was also able to initiate adenoma formation in wild-type mice. The combination of p27kip1 inactivation and the Western-style diet was additive in terms of tumor incidence, frequency and size, and in reducing the life span of the mice. The genetic and dietary combination also resulted in development of adenocarcinoma. Tumor formation was linked to a disruption in homeostasis of the intestinal mucosa, involving increased cell proliferation and decreased apoptosis. There was also decreased goblet cell differentiation as assessed by alcian blue staining and expression of the Muc2 gene, especially in mice fed the Western-style diet, although this differentiation lineage was still present as indicated by expression and staining for intestinal trefoil factor. The inactivation of p27kip1 and the consequent disruption of normal colonic cell maturation in the mucosa were associated with modestly elevated c-myc, cdk4, and cyclin D1 expression. These data establish a fundamental role for p27kip1 in maintenance of intestinal cell homeostasis and in suppressing tumor formation. The data also emphasize the critical role that dietary factors can have in both tumor initiation and progression through interaction with pathways that normally maintain intestinal homeostasis.

Original languageEnglish (US)
Pages (from-to)4990-4996
Number of pages7
JournalCancer Research
Volume63
Issue number16
StatePublished - Aug 15 2003

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Carcinogenesis
Diet
Homeostasis
Adenoma
Neoplasms
Staining and Labeling
Alcian Blue
Goblet Cells
Cyclin-Dependent Kinases
Cyclin D1
Intestinal Mucosa
Vitamin D
Cell Differentiation
Mucous Membrane
Adenocarcinoma
Fats
Alleles
Phosphates
Maintenance
Cell Proliferation

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Targeted inactivation of p27kip1 is sufficient for large and small intestinal tumorigenesis in the mouse, which can be augmented by a Western-style high-risk diet. / Yang, WanCai; Bancroft, Laura; Nicholas, Courtney; Lozonschi, Ioana; Augenlicht, Leonard H.

In: Cancer Research, Vol. 63, No. 16, 15.08.2003, p. 4990-4996.

Research output: Contribution to journalArticle

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