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Transforming Growth Factor –Dependent Cancer Progression Is Modulated by Muc1

¹ Department of Molecular and Cellular Biology, ² Arizona Cancer Center, and ³ Bio5 Institute, University of Arizona, Tucson, Arizona

Requests for reprints: Joyce A. Schroeder, Arizona Cancer Center, University of Arizona, 1515 North Campbell Avenue, P.O. Box 245024, Tucson, AZ 85724. Phone: 520-626-1384; Fax: 520-626-3764; E-mail: jschroeder{at}azcc.arizona.edu.

Transforming growth factor (TGF) is a potent inducer of cellular transformation, through its binding and activation of the epidermal growth factor receptor (EGFR). Previous studies in our laboratory showed that EGFR could also be affected by the glycoprotein MUC1, which inhibits ligand-stimulated degradation of EGFR in breast epithelial cell lines. To determine the effect of Muc1 expression on TGF/EGFR-dependent breast transformation, we crossed the WAP-TGF transgenic mouse model of breast cancer onto a Muc1-null background. We found that the loss of Muc1 expression dramatically affects mammary gland transformation and progression. Although 100% of WAP-TGF/Muc1^+/+ mice form mammary gland tumors by 1 year, only 37% of WAP-TGF/Muc1^–/– form tumors by this time. This difference is also associated with a delay in onset, with a doubling of onset time observed in the WAP-TGF/Muc1^–/– compared with the WAP-TGF/Muc1^+/+ mice. Analysis of signal transduction pathways revealed that activation of cyclin D1 expression is significantly suppressed in tumors derived from WAP-TGF/Muc1^–/– animals compared with those expressing Muc1. The loss of Muc1 expression also results in a significant inhibition in the formation of hyperplastic lesions during tumor progression. On the C57Bl/6 inbred background, pulmonary lesions were observed in 28 of 29 WAP-TGF/Muc1^+/+ animals (including one metastatic pulmonary adenocarcinoma and multiple perivascular lymphomas), although none were detected in the WAP-TGF/Muc1^–/– animals. Together, these data indicate that Muc1 is an important modulator of TGF-dependent tumor progression. [Cancer Res 2007;67(14):6591–8]

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