Abstract
Novel agents for the endocrine therapy of breast cancer are needed, especially in order to take advantage of the multiple consecutive responses observed in metastatic progressing breast cancer following previous hormone therapy, thus delaying the use of cytotoxic chemotherapy with its frequent poor tolerance and serious side effects. Acolbifene (ACOL) is a novel and unique antiestrogen which represents a unique opportunity to achieve the most potent and specific blockade of estrogen action in the mammary gland and uterus while exerting estrogen-like beneficial effects in other tissues, especially the bones. To better understand the specificity of action of ACOL, we have used Affymetrix GeneChips containing 45,000 probe sets to analyze 34,000 genes to determine the specificity of this compound compared to the pure antiestrogen fulvestrant, as well as to the mixed antagonists/agonists tamoxifen and raloxifene to block the effect of estradiol (E2) and to induce effects of their own on the genomic profile in the mouse mammary gland. The genes modulated by E2 were those identified in two separate experiments and validated by quantitative real-time PCR (qPCR). Three hours after the single subcutaneous injection of E2 (0.05 μg), the simultaneous administration of ACOL, fulvestrant, tamoxifen, and raloxifene blocked by 98, 61, 43, and 92 % the number of E2-upregulated genes, respectively. On the other hand, 70, 10, 25, and 55 % of the genes down-regulated by E2 were blocked by the same compounds. Of the 128 genes modulated by E2, 49 are associated with tumorigenesis while 22 are known to be associated with breast cancer. When used alone, ACOL modulated the smallest number of genes also influenced by E2, namely 4 %, thus possibly explaining potential utilities of this compound in breast cancer prevention and therapy.
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Acknowledgments
The authors wish to thank all the technicians and research assistants for their technical assistance for animal care and treatments. A special thanks to Annick Ouellet and Nathalie Paquet for probes preparation and qPCR quantification, respectively. This study was supported by Genome Canada and Genome Quebec.
Conflict of interest
Dr Fernand Labrie is President and CEO of EndoCeutics Inc. while the other authors are employees of Laval University Hospital Research Center and/or EndoCeutics Inc.
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Calvo, E., Luu-The, V., Belleau, P. et al. Specific transcriptional response of four blockers of estrogen receptors on estradiol-modulated genes in the mouse mammary gland. Breast Cancer Res Treat 134, 625–647 (2012). https://doi.org/10.1007/s10549-012-2104-7
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DOI: https://doi.org/10.1007/s10549-012-2104-7