We also demonstrate that dexamethasone pretreatment of breast malignancy cell lines inhibits chemotherapy-induced cytotoxicity and is associated with the transcriptional induction of clusterin. to clusterin or antisense clusterin oligodeoxynucleotides and paclitaxel, doxorubicin, or tamoxifen could be a novel and attractive strategy to inhibit the progression of breast carcinoma by regulation of the clusterin function. Moreover, glucocorticoid activation in breast malignancy cells regulates survival signaling by the direct transactivation of genes like clusterin which encode proteins that decrease susceptibility to apoptosis. Given the widespread clinical administration of dexamethasone before chemotherapy, understanding glucocorticoid-induced survival mechanisms is essential for achieving optimal therapeutic responses. Introduction Breast malignancy is the most frequently diagnosed malignancy in women today, and its incidence has continuously increased in recent decades. Resistance to anticancer chemotherapeutic drugs remains a major obstacle in malignancy chemotherapy, and novel therapeutic strategies that target the molecular basis of chemoresistance are required. In this sense, the response of cytotoxic Ethynylcytidine drugs is usually modulated by pro- and antiapoptotic proteins, and defects in apoptosis pathways or Ethynylcytidine the activation of antiapoptotic mechanisms may confer resistance to cytotoxic drug treatment. In fact, the downregulation of the CD-95 receptor/ligand system, deficient expression of caspase family members, or the overexpression of antiapoptotic bcl-2 protein have all been observed in drug-resistant tumors [1]. The clusterin protein is an inhibitor of apoptosis with a cytoprotective function [2] and thus represents a encouraging target for molecular intervention strategies such as antisense therapy designed to inhibit its expression [3]. The overexpression of exogenous clusterin has been shown to result in resistance to paclitaxel [4], doxorubicin [5], cisplatin [6], and radiation therapy [7]. In contrast, decreased clusterin expression by antisense or small interfering RNA (siRNA) expression enhances the chemosensitivities of various cell lines [8-11], suggesting that clusterin expression is usually a prominent resistance factor in malignancy cells. On the other hand, glucocorticoids (such as dexamethasone) are routinely used in the clinical application of chemotherapy to prevent adverse effects. A previous study reported the inhibitory action of glucocorticoids on chemotherapy-induced apoptosis, which also raises a clinically relevant question as to whether the pretreatment with glucocorticoids might interfere with the therapeutic efficacy of chemotherapy [12]. Glucocorticoids play a major role in attenuation of the inflammatory response. These steroid hormones are able to induce apoptosis in cells of the hematopoietic system such as the monocytes, macrophages, and T Ethynylcytidine lymphocytes that are involved in the inflammation reaction. In contrast, it has recently been discovered that in glandular cells such as the mammary gland epithelia, hepatocytes, and ovarian follicular cells and in fibroblasts, glucocorticoids protect against the apoptotic signals evoked by cytokines, cAMP, tumor suppressors, and death genes. It is well known that this antiapoptotic effect of glucocorticoids is usually exerted by the modulation of survival genes such as Bcl-2, Bcl-x(L), and nuclear factor-kappa B in a cell type-specific manner [13]. We hypothesize that clusterin may be one of these genes responsible for the antiapoptotic effect of glucocorticoids. Increased expression of the clusterin gene has been observed in breast malignancy cells and has been associated with the development and progression of these tumors [14]. Moreover, clusterin overexpression has been shown to be associated with the anti-HER-2 antibody trastuzumab (Herceptin) treatment resistance through the inhibition of apoptosis [15]. To explore the potential of the clusterin inhibition approach in breast malignancy therapy, the cytotoxic conversation between antisense clusterin oligonucleotide or anticlusterin antibody and the drugs commonly used in breast cancer treatment such as dexamethasone, doxorubicin, paclitaxel, Fndc4 and tamoxifen were analyzed in vitro using the breast carcinoma cell lines MCF-7 and MDA-MB-231. Materials and methods Cell lines Estrogen-independent MDA-MB-231 and estrogen-dependent MCF-7 breast malignancy cell lines were obtained from the American Type Culture Collection (Manassas,.