Carcinogenesis Advance Access published online on January 10, 2006
Carcinogenesis, doi:10.1093/carcin/bgi341
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1 Department of Surgery and The Alvin J. Siteman Cancer Center, Campus Box 8109, 660 S. Euclid Avenue, Washington University School of Medicine, St. Louis, MO 63110
* To whom correspondence should be addressed. Rats treated with the alkylating agent MNU develop multiple hormonally dependent tumors. Roughly 50% of the tumors have Ha-ras mutation while 50% do not. The MNU induced rat mammary tumor model was employed to examine the therapeutic efficacy of the farnesyltransferase inhibitor (FTI), R115777, and to examine the use of genomics in identifying susceptible tumors as well as identifying genes whose expression are modulated by FTI treatment. In animals bearing palpable mammary tumors (<7 mm diameter), we performed a surgical biopsy and three days following the biopsy rats were treated with R115777 (50 mg/KgBW/day) by gavage. Tumors with Ha-ras mutations underwent profound regression, with nearly 90% showing complete regressions within 4 weeks. In contrast, the non Ha-ras mutation-bearing tumors yielded a more variable response although roughly half of the non Ha-ras mutations tumors underwent significant regression. These results show that although all tumors appear to respond to the FTI inhibitor the tumors with Ha-ras mutations were exquisitely sensitive. We employed a microarray approach to define potential targets and the mechanism of action of R115777 in Ha-ras positive or negative tumors following treatment with FTI. In addition we determined whether gene expression prior to FTI treatment can be used to differentiate highly sensitive tumors (Ha-ras positive) and tumors with variably sensitivity (Ha-ras negative). Untreated or FTI treated (4 days at 50 mg/KgBW) tumors (Ha-ras positive or negative) were examined using oligonucleotide arrays. A significant number of genes were differentially expressed in control rat mammary tumors with or without an activated Ha-ras mutation, suggesting that a microarray analysis might differentiate highly sensitive and variably sensitive tumors. Most of the genes whose expressions were modulated by FTI in tumors were independent of Ha-ras status. and were presumably modulated by effects on farnesylation of proteins other than Ha-ras. However treatment of Ha-ras mutated mammary tumors with R155777 results in preferential modulation of genes involved in ras-MAP kinase signal transduction pathway and in decreased expression of many genes involved with cell proliferation. In contrast, several classes of genes that are altered in rat mammary tumors without an activated Ha-ras, suggesting that non-ras targets are involved. Ras pathway related genes, p53, WT1, and PCNA were preferentially modulated in Ha-ras activated tumors, whereas modulation of genes in the G-protein pathway, various cytochrome p450s, and RB1 are involved in Ha-ras negative tumors. Elucidation of gene expression changes in FTI treated or control rat mammary adenocarcinomas will help to identify potential pharmacodynamic markers of FTI tretment as well as potential molecular targets of R115777 and other farnesyltransferase inhibitors.
Received August 18, 2005
Revised October 24, 2005
Accepted January 3, 2006
MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION
Efficacy of the farnesyltransferase inhibitor R115777 in a rat mammary tumor model: Role of Ha-ras mutations and use of microarray analysis to identify potential targets
Ruisheng Yao 1,
Yian Wang 1,
Yan Lu 1,
William J. Lemon 1,
David W. End 2,
Clinton J. Grubbs 3,
Ronald A. Lubet 4,
and
Ming You 1 *
2 Janssen Research Foundation, Spring House, Pennsylvania 19477
3 Chemoprevention Center, University of Alabama at Birmingham, Birmingham, Alabama 35294
4 Chemoprevention Branch, National Cancer Institute, Bethesda, Maryland 20892
Ming You, E-mail: youm{at}msnotes.wustl.edu
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