Estrogen-induced dimerization and activation of ERα-fused caspase-8: Artificial reversal of the estrogenic hormone effect in carcinogenesis

Targeted Apoptosis in Breast Cancer Immunotherapy

“…Estradiol also significantly impaired the development of the xenograft breast cancers derived from the chimeric gene-modified SKBr-3 cells, and inhibited the growth of in vivo tumors originating from MCF-7 cells when administered in combination with the chimeric gene recombinant adenovirus (Zhao et al, 2011). Unlike previously reported artificial caspase recruitment models, our study employed the receptor of endogenous estrogenic hormones, which otherwise promote the growth of breast cancer cells, to trigger the apoptotic signaling in breast cancers, thus switching the estrogenic hormones from potential mitogens to apoptosis inducers in breast cancers (Shi, 2004;Zhao et al, 2011). Therefore, the caspase-8 and estrogen receptor-based chimeric protein has implications in developing novel therapeutics of estrogen-dependent andindependent breast cancers.…”

“…Therefore, the caspase-8 and estrogen receptor-based chimeric protein has implications in developing novel therapeutics of estrogen-dependent andindependent breast cancers. Despite the effectiveness of the chimeric protein, optimization of this suicidal system using an accurate dimerization-related domain of ER is necessary for preventing inappropriate autoactivation of chimeric caspase-8; given that the estrogen antagonist, tamoxifen, is also found to induce the formation of ER dimers in a much lower efficiency, it remains elusive whether tamoxifen in place of estradiol could trigger dimerization and activation of caspase-8 conjugated to the ER ligand-binding domain (Tamrazi et al, 2002;Zhao et al, 2011). In addition to the generation of fusion/chimeric proteins, the pro-apoptotic gene regulatory elements, as well as the gene construct carriers, either non-viral or viral particles, have also been modified to target breast cancers.…”

“…Upon administration of estrogen, the fusion protein will be induced to form a dimer, which triggers the activation of caspase-8 and apoptosis (Tamrazi et al, 2002;Shi, 2004). Indeed, incubation of estradiol with the chimeric gene-modified breast cancer cells induced a rapid dimerization of the chimeric protein, which in turn caused the activation of caspase-8 within the chimeric protein and leads to apoptosis of the modified cells (Zhao et al, 2011). Estradiol also significantly impaired the development of the xenograft breast cancers derived from the chimeric gene-modified SKBr-3 cells, and inhibited the growth of in vivo tumors originating from MCF-7 cells when administered in combination with the chimeric gene recombinant adenovirus (Zhao et al, 2011).…”

“…Indeed, incubation of estradiol with the chimeric gene-modified breast cancer cells induced a rapid dimerization of the chimeric protein, which in turn caused the activation of caspase-8 within the chimeric protein and leads to apoptosis of the modified cells (Zhao et al, 2011). Estradiol also significantly impaired the development of the xenograft breast cancers derived from the chimeric gene-modified SKBr-3 cells, and inhibited the growth of in vivo tumors originating from MCF-7 cells when administered in combination with the chimeric gene recombinant adenovirus (Zhao et al, 2011). Unlike previously reported artificial caspase recruitment models, our study employed the receptor of endogenous estrogenic hormones, which otherwise promote the growth of breast cancer cells, to trigger the apoptotic signaling in breast cancers, thus switching the estrogenic hormones from potential mitogens to apoptosis inducers in breast cancers (Shi, 2004;Zhao et al, 2011).…”

“…This model has been applied in developing pro-apoptotic strategies in cancer treatment based on the oligomerization capacity of either mouse IgG Fc portion or the tandem FK506-binding domain (FKBP) plus its dimeric ligand FK1012 (Muzio et al, 1998;Shi, 2004;Srinivasula et al, 1998b). In a study focusing on ER-positive breast cancer treatment, we generated a fusion gene encoding the chimeric protein of caspase-8 and the ligand-binding domain (LBD) of ER and introduced the gene into breast cancer cell lines (Zhao et al, 2011). Upon administration of estrogen, the fusion protein will be induced to form a dimer, which triggers the activation of caspase-8 and apoptosis (Tamrazi et al, 2002;Shi, 2004).…”