M. Goetz, X. Hou, V. Suman
Dec 15, 2011
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Cancer Research
Abstract
Background: First in human studies of Z-endoxifen hydrochloride (E), the active metabolite of tamoxifen (T), are underway in metastatic breast cancer (BC). Previous data have demonstrated the superiority of aromatase inhibitors (AI9s) over T in estrogen receptor (ER) + BC. Using an in vivo aromatase expressing model (MCF7/AC1), we compared the antitumor activity of E with T and Letrozole (L), as well as the antitumor activity and global gene expression changes of E with T in an L-resistant model. Methods: MCF7/AC1 tumors were stimulated with androstenedione. Once tumor size reached 300 mm 3 , mice (30/group) were randomly assigned to one of five treatment groups: control (daily, po), T (500 μg/day, sc), endoxifen 25 mg/kg/day p.o.(LDE) endoxifen 75 mg/kg/day p.o. (HDE) or letrozole, 10 μg/day s.c for 4 weeks. Tumors were harvested from control, T, and E groups while the L group continued treatment until the development of resistance defined as an increase in tumor volume of at least 300% from day 1. Mice with L-resistant tumors were randomly assigned to T (n=4) or E (n=5) for 4 weeks and then sacrificed. Gene expression in L-resistant tumors was quantified using Affymetrix U133+2 and changes in gene expression profiles [comparing T and E with L-resistant (n=3)] were analyzed. Genes identified as significantly different were confirmed by real-time RT-PCR assays. Results: At the 4 week time point, both doses of E and L resulted in greater anti-tumor activity than control (Wilcoxon rank sum test: all p PGR ) and amphiregulin ( AREG ) that were significantly down-regulated in the E group [PGR (−6.2 fold, p=0.000008) and AREG (−3.2 fold, p=.0006) but unchanged or up-regulated in the T group (PGR unchanged and AREG +9.2 fold p=0.00002). These findings were confirmed by RT-PCR. Conclusions: Using the MCF7/AC1 model previously used to show the superiority of AI9s over T, HDE demonstrated similar antitumor activity to L and was superior to T. In cells resistant to L, E was superior to T and gene expression changes demonstrate that E down-regulates while T activates estrogen regulated genes. These findings support the ongoing development of E for the treatment of ER+ BC. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD01-06.