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¹ Lineberger Comprehensive Cancer Center; ² Department of Pharmacology; and ³ Cystic Fibrosis/Pulmonary Research and Treatment Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; ⁴ Faculty of Medical Science, University of Fukui, Fukui, Japan; and ⁵ Seattle Genetics, Inc., Bothell, Washington

Requests form reprints: Jozef Spychala, Department of Pharmacology, University of North Carolina, MEJ Building, CB7365, Chapel Hill, NC 27599-7365. Phone: 919-493-8996; Fax: 919-493-3299. E-mail: jozekspy{at}visiscience.com

Recently, we have found dramatic overexpression of ecto-5'-nucleotidase (or CD73), a glycosylphosphatidylinositol-anchored component of lipid rafts, in estrogen receptor–negative [ER(–)] breast cancer cell lines and in clinical samples. To find out whether there is a more general shift in expression profile of membrane proteins, we undertook an investigation on the expression of selected membrane and cytoskeletal proteins in aggressive and metastatic breast cancer cells. Our analysis revealed a remarkably uniform shift in expression of a broad range of membrane, cytoskeletal, and signaling proteins in ER(–) cells. A similar change was found in two in vitro models of transition to ER(–) breast cancer: drug-resistant Adr2 and c-Jun-transformed clones of MCF-7 cells. Interestingly, similar expression pattern was observed in normal fibroblasts, suggesting the commonality of membrane determinants of invasive cancer cells with normal mesenchymal phenotype. Because a number of investigated proteins are components of lipid rafts, our results suggest that there is a major remodeling of lipid rafts and underlying cytoskeleton in ER(–) breast cancer. To test whether this broadly defined ER(–) phenotype could be reversed by treatment with differentiating agent, we treated ER(–) cells with trichostatin A, an inhibitor of histone deacetylase, and observed reversal of mesenchymal and reappearance of epithelial markers. Changes in gene and protein expression also included increased capacity to generate adenosine and altered expression profile of adenosine receptors. Thus, our results suggest that during transition to invasive breast cancer there is a significant structural reorganization of lipid rafts and underlying cytoskeleton that is reversed upon histone deacetylase inhibition. [Mol Cancer Ther 2006;5(2):238–45]

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Received 7/ 5/05; revised 11/29/05; accepted 12/16/05.

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