International Mammalian Genome Society

logo18th International Mouse Genome Conference

17-22 October 2004, Seattle, USA


POSTER 188- STUDYING THE INDUCTION OF MAMMARY TUMOR FORMATION IN TRANSGENIC MICE EXPRESSING PHOSPHO-MUTANT BETA-CATENIN

Kockeritz LK 1, Wood GA 2, Done SJ 3, Woodgett JR 1

1 Department of Medical Biophysics, University of Toronto, Toronto, Canada, 2 Department of Pathobiology, University of Guelph, Guelph, Canada, 3 Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada

The Wnt signaling pathway results in the activation of beta-catenin, a transactivator that works with members of the Tcf/LEF family of transcription factors to drive gene transcription.  Negative regulators of beta-catenin are frequently mutated in human cancer, resulting in inappropriate beta-catenin activation and subsequent gene expression of various downstream targets including many oncogenes.  Activating mutations of beta-catenin itself has also been found in a variety of human tumors. Here we illustrate that a phosphomutant version, typical of what is seen in human cancers, can induce mammary tumor formation in mice.

The development of mammary tumors in our MMTV-beta-catenin phosphomutant (S33, 37, 41, 45A) occurs at a higher frequency in multiparous females than in nulliparous mice, suggesting hormonal influences are at play. Considering that the background strain of mice, FVB, tend to develop prolactin-secreting pituitary adenomas that induce lobuloalveolar development typically seen in pregnant females and that 92% of tumor-bearing females exhibit moderate to extreme lactational changes in non-tumor bearing mammary glands, we are currently investigating a link between prolactin and beta-catenin signaling.  We hypothesize that beta-catenin signaling requires the increase in cellular proliferation provided by prolactin for tumors to develop.  By using microarray and immunohistochemical analyses of tumors developed in our model we hope to better understand the molecular mechanisms of aberrant beta-catenin signaling in cancer development.

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