Endocrine resistance is a major obstacle to hormonal therapy for breast cancers. Although reduced expression of estrogen receptor-α (ER-α) is a known contributing factor to endocrine resistance, the mechanism of ER-α downregulation in endocrine resistance is still not fully understood. Here we report that CUE domain-containing protein-2 (CUEDC2), a ubiquitin-binding motif-containing protein, is a key factor in endocrine resistance in breast cancer. We show that CUEDC2 modulates ER-α protein stability through the ubiquitin-proteasome pathway. Through the study of specimens from a large cohort of subjects with breast cancer, we found a strong inverse correlation between CUEDC2 and ER-α protein expression. Notably, subjects with tumors that highly expressed CUEDC2 had poor responsiveness to tamoxifen treatment and high potential for relapse. We further show that ectopic CUEDC2 expression impaired the responsiveness of breast cancer cells to tamoxifen. Therefore, our findings suggest that CUEDC2 is a crucial determinant of resistance to endocrine therapies in breast cancer.

Shortening of the telomeric DNA at the chromosome ends is presumed to limit the lifespan of human cells and elicit a signal for the onset of cellular senescence. To continually proliferate across the senescent checkpoint, cells must restore and preserve telomere length. This can be achieved by telomerase, which has the reverse transcriptase activity. Telomerase activity is negative in human normal somatic cells but can be detected in most tumor cells. The enzyme is proposed to be an essential factor in cell immortalization and cancer progression. In this review we discuss the structure and function of telomere and telomerase and their roles in cell immortalization and oncogenesis. Simultaneously the experimental studies of telomerase assays for cancer detection and diagnosis are reviewed. Finally, we discuss the potential use of inhibitors of telomerase in anti-cancer therapy.Key words: Telomere, telomerase, cancer, telomerase assay, inhibitor. REVIEWTelomere and cell replicative senescence Telomeres, which are located at the end of chromosome, are crucial to protect chromosome against degeneration, rearrangment and end to end fusion [1]. Human telomeres are tandemly repeated units of the hexanucleotide TTAGGG. The estimated length of telomeric DNA varies from 2 to 20 kilo base pairs, depending on factors such as tissue type and human age. The buck of telomeric DNA is doublestranded, but the end of telomeric DNA consists of 3' overhang of single-stranded repeats. Sequencespecific DNA-binding proteins (TRF1 and TRF2) attach to the telomeric DNA repeats. These proteins help maintain telomere stability and regulate telomere length [2].Owing to the nature of lagging-strand DNA synthesis, traditional DNA polymerases are unable to completely replicate the ends of linear DNA [3]. Incomplete replication leads to the loss of 50-200 base pairs of the end of telomeric DNA with each round of DNA replication. Hence, the continual cycles of cell growth and division bring on progressing telomere shortening [4]. Now it is clear that telomere shortening is responsible for inducing the senescent phenotype that results from repeated cell division, but the mechanism how a short telomere induces the senescence is still unknown. Possible mechanism includes the short telomere inducing a DNA damage response, releasing transcriptional regulatory factors from sequestration, and relaxing heterochromatin which can lead to the arrest of cell growth and the cell senescence [5]. Senescence represents a state in which cells no longer proliferate but remain viable for extended periods. The cells which are about to enter the senescent state can be induced to bypass senescence through the introduction of viral oncogenes such as SVA40 Large T antigen (LT) and the HPV E6 or E7 protein. These viral proteins can inactivate p53 and Rb tumor suppressor pathways, which play a pivotal role in inducing the senescence phenotype. These cells that bypass senescence state continue to proliferate and suffer from further telomere loss. So the shortening

Hindlimb unloading (HU) in rodent is a well-accepted ground-based model used to simulate some of the conditions of space flight and reproduce its deleterious effects on the musculoskeletal, cardiovascular and immune systems. In this study, the effects of HU on lymphocyte homeostasis in the spleen and thymus of mice were examined. HU was found to drastically deplete various cell populations in the spleen and thymus. These changes are likely to be mediated by apoptosis, since DNA strand breaks indicative of apoptosis were detected by terminal deoxynucleotidyl transferase-mediated nick end-labeling in both splenocytes and thymocytes. Surprisingly, administration of opioid antagonists or interference with the Fas-FasL interaction was able to block HU-induced reductions of splenocytes, but not thymocytes. On the other hand, steroid receptor antagonists blocked the reduction of lymphocyte numbers in both spleen and thymus. Therefore, the effects of HU on the homeostasis of splenocytes and thymocytes must be exerted through distinct mechanisms.

Hepatitis B virus (HBV) infection is a risk factor for hepatocarcinogenesis and recurrence. Here, we sought to characterize intratumoral and peritumoral expression of HBsAg and its specific receptors in HBsAg-positive hepatocellular carcinoma (HCC) patients and further examined their correlation with the recurrence-free survival (RFS). HCC tissue and adjacent normal tissue specimens were acquired from HBsAg-positive patients. The presence of HBsAg and receptors, as well as hepatic progenitor cells (HPCs) were detected by tissue microassay and immunohistochemistry. Necroinflammatory activity was evaluated by HE staining. The mean IOD of HBsAg and HBV DNA in the intratumoral tissues was markedly lower than that in the peritumoral tissues (P < 0.001). Pearson correlation analysis further showed a significant correlation between the expression of HBsAg and NTCP (r = 0.461, P < 0.001) or ASGPR (r = 0.506, P < 0.001) in peritumoral tissues. And the peritumoral HBsAg and receptors presented a positive association with necroinflammatory activity (P < 0.05). Inflammation induced by HBV infection presented a positive association with HPCs activation (P < 0.05). Additionally, due to lack of HBV receptors, HPCs was not preferentially infected with HBV, but activated HPCs had a significant correlation with HBsAg expression in peritumoral tissues, and the peritumoral HPCs activation was associated with RFS of HCC patients, therefore, the overexpression of HBsAg and receptors in peritumor were also with higher recurrence risk (P < 0.05). In conclusion, lack of HBV receptors resulted in scant HBV infection in tumor cells, and overexpression of HBsAg and receptors in peritumor was strongly associated with higher recurrence risk in HCC patients.