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Effects of Novel Retinoic Acid Metabolism Blocking Agent (VN/14-1) on Letrozole-Insensitive Breast Cancer Cells

Department of Pharmacology and Experimental Therapeutics, School of Medicine and the Greenebaum Cancer Center, University of Maryland, Baltimore, Maryland

Requests for reprints: Vincent C.O. Njar, Department of Pharmacology and Experimental Therapeutics, School of Medicine, University of Maryland, 655 West Baltimore Street, Baltimore, MD 21201-1559. Phone: 410-706-5885; Fax: 410-706-0032; E-mail: vnjar001{at}umaryland.edu.

Aromatase inhibitors are proving to be more effective than tamoxifen for postmenopausal estrogen receptor (ER)-positive breast cancer. However, the inevitable development of resistance to treatment is a concern. We investigated the effects of novel retinoic acid metabolism blocking agent, VN/14-1, in overcoming letrozole resistance in long-term letrozole cultured (LTLC) cells. Compared with MCF-7 cells stably transfected with aromatase (MCF-7Ca), LTLC cells were no longer sensitive to growth inhibition by aromatase inhibitors. The HER-2/phosphorylated mitogen-activated protein kinase (pMAPK) growth factor signaling pathways were activated, and ER and coactivator amplified in breast cancer 1 (AIB1) were up-regulated 3-fold in LTLC cells. VN/14-1 inhibited aromatase activity and growth values of in MCF-7Ca cells with IC₅₀ of 8.5 and 10.5 nmol/L, respectively. In human placental microsomes, aromatase activity was inhibited with IC₅₀ of 8.0 pmol/L. The IC₅₀ in LTLC cells was 0.83 nmol/L, similar to letrozole (IC₅₀, 0.3 nmol/L) in MCF-7Ca cells. LTLC cells were 10-fold more sensitive to growth inhibition by VN/14-1 than MCF-7Ca cells. VN/14-1 treatment effectively down-regulated ER, AIB1, pMAPK, HER-2, cyclin D1, cyclin-dependent kinase 4 (CDK4), and Bcl2 and up-regulated cytokeratins 8/18, Bad, and Bax. Tumor growth of LTLC cells in ovariectomized nude mice was independent of estrogens but was inhibited by VN/14-1 (20 mg/kg/d; P < 0.002). Decreases in ER, cyclin D1, CDK4, and pMAPK and up-regulation of cytokeratins, Bad, and Bax with VN/14-1 in tumor samples may be responsible for the efficacy of this compound in inhibiting LTLC cell growth in vitro and in vivo. (Cancer Res 2006; 66(23): 11485-93)