Abstract
Abstract Introduction: Acolbifene (ACOL) is a novel compound completely free of estrogen-like activity in both the human and rat mammary gland and uterus. In previous studies, it was observed that ACOL could have a cytotoxic or tumoricidal rather only tumorostatic activity, with a lack of development of tumor resistance. The objective of the present study was to obtain information on the molecular basis of the tumoricidal properties of acolbifene, as well as on the identity of the genes potentially implicated in the resistance to tamoxifen (TAM). The specificity of action of ACOL was compared to the pure antiestrogen fulvestrant (FUL) as well as to tamoxifen (TAM) and raloxifene (RAL). Methods: The gene expression profile of the ZR-75-1 breast cancer xenografts was studied following treatment with ACOL, RAL, TAM and FUL. Ovariectomized female nude mice (10/group) bearing human ZR-75-1 breast cancer xenografts were supplemented with estrone (E1) (subcutaneous silastic implants) and were injected daily with the vehicle alone or 50 μg of ACOL, RAL, TAM or FUL for 6 months. Mice were killed 24h after the last injection and ZR-75-1 tumors were collected and processed for RNA extraction and microarray analyses (Affymetrix GeneChip U133 Plus 2.0). Results: Long-term exposure of ZR-75-1 xenografts to E1 causes a massive modulation of E1-responsive genes. When the antiestrogens were administered simultaneously with E1, some compound-specific prevention of the effect of E1 was observed. Globally, the efficacy of the compounds was ACOL>FUL or RAL>TAM. ACOL significantly prevented the effect of E1 on 195 responsive genes. Among these, the most enriched gene ontological group in Molecular Function was Receptor Activity, including ER, insulin, retinoid and thrombospondin receptor activity. One of the transcriptional repressors of the estrogen signaling pathway, the NKX31, was down-regulated by E1 and completely blocked by ACOL (fold-change −1.64 and 2.54, respectively). The most enriched biological processes were associated with mammary gland development, positive regulation of glucose metabolic processes and blood vessel morphogenesis. Between the genes implicated in cell death/apoptosis of breast cancer cells, the changes of expression of 57, 51, 48 and 31 genes were significantly neutralized by ACOL, RAL, FUL and TAM, respectively. Sixteen genes implicated in tumor resistance to TAM were significantly blocked by ACOL, including DEGS1, a gene implicated in the inhibition of EGF receptor biosynthesis. The other 15 genes in the group were up-regulated by E1, changes which were significantly blocked by ACOL. Conclusion: The present data offer a possible explanation for the potent tumoricidal action of acolbifene in human breast cancer xenografts, thus offering a new paradigm in the hormonal therapy of breast cancer. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-06-03.
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