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Cyclin D1 Overexpression Sensitizes Breast Cancer Cells to Fenretinide

Trescowthick Research Laboratories [A. P., J. H., M. J. O., D. G.] and Statistical Centre [K. Y.], Peter MacCallum Cancer Institute, St. Andrew’s Place, East Melbourne, Victoria, 3002, and Department of Biochemistry and Molecular Biology, University of Melbourne, Victoria, 3010 [D. G.], Australia

Purpose: Fenretinide has shown promise in the chemoprevention of breast cancer, a tumor type in which the oncogene cyclin D1 is overexpressed frequently. We aimed at determining the effect of cyclin D1 level on the response to fenretinide treatment.

Experimental Design: Stable clones of T47-D cells were created to overexpress cyclin D1 or a mutant of cyclin D1, injected in nude mice for xenograft formation, and the rate of tumor growth and tumor regression determined.

Results: We show here that cells overexpressing cyclin D1 are significantly more sensitive to fenretinide than genetically matched cells that express low levels of cyclin D1, and that fenretinide prevents tumor formation arising from cyclin D1-overexpressing cells. Furthermore, we show that fenretinide is also able to promote the regression of cyclin D1-positive tumors. We also show that cells expressing a mutant of cyclin D1 that cannot bind to cdk4 are also more sensitive to fenretinide.

Conclusions: These results suggest that fenretinide may be particularly useful in the treatment of cyclin D1-positive breast cancers, and that the interaction between cyclin D1 and fenretinide is independent of cyclin D1 binding to cdk4.

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