Human X-box binding protein-1 (XBP1) is an alternatively spliced transcription factor that participates in the unfolded protein response (UPR), a stress-signaling pathway that allows cells to survive the accumulation of unfolded proteins in the endoplasmic reticulum lumen. We have previously demonstrated that XBP1 expression is increased in antiestrogen-resistant breast cancer cell lines and is coexpressed with estrogen receptor alpha (ER) in breast tumors. The purpose of this study is to investigate the role of XBP1 and the UPR in estrogen and antiestrogen responsiveness in breast cancer. Overexpression of spliced XBP1 [XBP1(S)] in ER-positive breast cancer cells leads to estrogen-independent growth and reduced sensitivity to growth inhibition induced by the antiestrogens Tamoxifen and Faslodex in a manner independent of functional p53. Data from gene expression microarray analyses imply that XBP1(S) acts through regulation of the expression of ER, the antiapoptotic gene BCL2, and several other genes associated with control of the cell cycle and apoptosis. Testing this hypothesis, we show that overexpression of XBP1(S) prevents cell cycle arrest and antiestrogen-induced cell death through the mitochondrial apoptotic pathway. XBP1 and/or the UPR may be a useful molecular target for the development of novel predictive and therapeutic strategies in breast cancer.

Caveolin-1 (CAV1), a highly conserved membrane-associated protein, is a putative regulator of cellular transformation. CAV1 is localized in the plasmalemma, secretory vesicles, Golgi, mitochondria, and endoplasmic reticulum membrane and associates with the microtubule cytoskeleton. Taxanes such as paclitaxel (Taxol) are potent anti-tumor agents that repress the dynamic instability of microtubules and arrest cells in the G 2 /M phase. Src phosphorylation of Tyr-14 on CAV1 regulates its cellular localization and function. We report that phosphorylation of CAV1 on Tyr-14 regulates paclitaxel-mediated apoptosis in MCF-7 breast cancer cells. Befitting its role as a multitasking molecule, we show that CAV1 sensitizes cells to apoptosis by regulating cell cycle progression and activation of the apoptotic signaling molecules BCL2, p53, and p21. We demonstrate that phosphorylated CAV1 triggers apoptosis by inactivating BCL2 and increasing mitochondrial permeability more efficiently than non-phosphorylated CAV1. Furthermore, expression of p21, which correlates with taxane sensitivity, is regulated by CAV1 phosphorylation in a p53-dependent manner. Collectively, our findings underscore the importance of CAV1 phosphorylation in apoptosis and suggest that events that negate CAV1 tyrosine phosphorylation may contribute to anti-microtubule drug resistance. Caveolin-1 (CAV1)2 is a 21-24-kDa protein and the prototype of a family of integral membrane proteins that associate with specific cholesterol-and sphingolipid-rich domains to form the structural foundation of membrane invaginations called caveolae. Caveolae act as sites of signal transduction in various cell types (1). CAV1 is thought to regulate the activity of proteins such as Src kinases, epidermal growth factor tyrosine kinase, Her2/neu (ErbB2) kinase, ERK (extracellular signal-regulated kinase), H-Ras, endothelial nitric-oxide synthase, and G proteins (1, 2) involved in survival pathways. In human breast tumors, CAV1 levels inversely correlate with tumor size (3), and CAV1 expression reduces the growth of mouse mammary tumors and their spontaneous metastasis to lung and bone (4). However, in breast cancer cell culture models, CAV1 is downregulated in non-invasive human breast cancer cells but upregulated in cells with an invasive phenotype (5-7).Taxanes are potent anti-tumor agents that function by binding to the ␤ subunits of tubulin and repressing the dynamic instability of spindles (8, 9), activities that lead to cell cycle arrest in the G 2 /M phase (10). Taxanes such as paclitaxel (Taxol) or docetaxel (Taxotere) are routinely used in the firstline treatment of metastatic breast, lung, ovarian, and digestive cancers (11). In primary breast cancer, inclusion of taxane in adjuvant chemotherapy reduces the relative risk of recurrence and improves overall survival (12). Acquired resistance through cellular adaptations or mutations in neoplastic cells remains a major problem in chemotherapy. Although taxanes are substrates for ABC transporters, other resistance mechanis...

Backgrounds-p53 is a tumor suppressor that prevents cancer onset and progression, and mutations in the p53 gene cause loss of the tumor suppressor function of the protein. The mutant p53 protein in tumor cells can form aggregates which contribute to the dominant-negative effect over the wild-type p53 protein, causing loss of p53 tumor suppression or gain of novel oncogenic functions. Mutations in p53 have been implicated in the pathogenesis of primary prostate cancer (PCa), and are often detected in recurrent and metastatic disease. Thus, targeting mutant p53 may constitute an alternative therapeutic strategy for advanced PCa for which there are no other viable options.Methods-In this study, we used immunoprecipitation, immunoflurorenscence, clonogic survival and cell proliferation assays, flow cytometric analysis and in vivo xenograft to investigate the biological effects of ReACp53, a cell-permeable peptide inhibitor of p53 aggregation, on mutant p53-carrying PCa cells.Results-Our results show that ReACp53 targets amyloid aggregates of mutant p53 protein and restores the p53 nuclear function as transcriptional factor, induces mitochondrial cell death and reduces DNA synthesis of mutant p53-carrying PCa cells; ReACp53 also inhibits xenograft tumor growth in vivo.Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

Background: This study sought to detect the expression and clinical significance of miR-4516 and miR-21-5p in serum of patients with colorectal cancer. Methods: Bioinformatics methods were used to analyze the expression patterns of miR-4516 and miR-21-5p in colorectal cancer. A total of 80 patients with colorectal cancer, 65 patients with benign colorectal tumors and 50 healthy persons were selected. qRT-PCR was performed to detect the expression levels of serum miR-4516 and miR-21-5p before and after operation or postoperative recurrence. The correlation of miR-4516 and miR-21-5p expression levels with the clinical characteristics and prognosis of colorectal cancer was analyzed, and that with the patient's survival was further examined by Kaplan-Meier analysis. Results: MiR-4516 was poorly expressed in colorectal cancer in the preoperative group, and miR-21-5p was highly expressed. While in the postoperative group, miR-4516 was up-regulated, and miR-21-5p was down-regulated. The low expression of miR-4516 was shown to be related to TNM staging, invasion degree, lymph node metastasis and distant metastasis of the patients. Whereas the high expression of miR-21-5p was proved to be correlated with TNM staging and lymph node metastasis. Kaplan-Meier survival analysis showed that high expression of miR-4516 or low expression of miR-21-5p could contribute to better overall survival. Conclusion: Low miR-4516 or high miR-21-5p could be used as an independent risk factor for prognosis of colorectal cancer.